3-aminoquinazolin-2,4-dione antibacterial agents

ABSTRACT

Antibacterial 3-aminoquinazolin-2,4-diones have formula (I) wherein: R 1  and R 3  include alkyl, alkenyl, cycloalkyl, aryl, hetero-cyclic, and heteroaryl; R 5 , R 6 , and R 8  include H, alkyl, alkoxy, halo, NO 2 , CN, NH 2 , alkyl and dialkylamino; R 7  includes hydrogen, alkyl, cycloalkyl, hetero-cyclic, fused heterocyclic, aryl and fused aryl; J and K are C or N; and pharmaceutically acceptable salts thereof.

This application is a 371 of PCT/US00/33656 filed Dec. 12, 2000 whichclaims the benefit of U.S. Provisional Application No. 60/241,267 filedOct. 18, 2000 and 60/178,252 filed Jan. 24, 2000.

FIELD OF THE INVENTION

This invention relates to 3-aminoquinazolin-2,4-diones that have potentin vitro and in vivo antibacterial activity. In addition, this inventionrelates to a method of inhibiting both wild-type and quinolone resistantmutants of DNA gyrase. This invention further relates to a method oftreating patients having antibiotic resistance and in need of treatmentfor bacterial infections.

BACKGROUND OF THE INVENTION

Antibiotic resistance is a worldwide problem with catastrophicpotential. The American Society of Microbiology Task Force recentlyissued a report defining the resistance problem and calling for newantibacterial agents with novel structures or mechanisms to offeralternatives to existing therapeutic choices (Southern Med. J, 1995;88:797).

The quinolones are a class of antibacterials that are widely usedthroughout the world. The quinolones are potent inhibitors of grampositive and gram negative bacteria, and may be administered orally orintravenously. The quinolones are routinely used even though they haveside effects (J. Antimicrob. Chemother., 1994; 33:685), and significantresistance has been frequently noted (Gootz, Medicinal Research, 1996;Rev. 16:433). One of the most widely used quinolones is ciprofloxacin,which has the following chemical structure:

The quinolones have a distinct structure activity relationship (SAR)which is defined by several thousands of analogs prepared over the last30 years (S. Mitsuhashi, ed. Progress in Drug Research, 1992;38:11–147). In the quinolone SAR (referring to the formula belowrepresenting substituted quinolones), it is well-established that the N₁group, in combination with the C₃-carboxyl and the C₄-carbonyl, areessential for activity, and that any substituents at C₂ detract fromactivity (J. Antimicrob. Chemother, 1994; 33:685 and Gootz, supra.,1996). It is also well-established that R₆ is ideally fluorine, and thatR₇ is a nitrogen containing heterocycle. R₁ is ideally a small alkyl, acycloalkyl, or a phenyl group.

The quinolones inhibit bacterial growth by inhibition of DNA gyrase andtopoisomerase IV (Gootz, supra., 1996). The gyrase interaction appearsto rely on the N₁/C₄-carbonyl/C₃-carboxyl relationship.

Attempts to design novel quinolone mimics have focused on theN₁/C₄-carbonyl/C₃-carboxyl relationship. Certain tricyclic isothiazoleanalogs were designed to keep an all-planar relationship, and to havethe NH of the isothiazole ring be as acidic as the quinolone C₃-carboxylgroup (Chu, Drugs Exptl. Clin. Res., 1990; 16:215).

While maintaining excellent antibacterial activity, these compounds alsoshow antitumor and mammalian topoisomerase activity (Drugs of theFuture, 1992; 17:1101). These activities are undesired in anantibacterial agent.

Several publications (U.S. Pat. No. 5,283,248; J. Med. Chem., 1992;35:1358; Antimicrob. Agents Chemother., 1995; 39:163) disclose tricycliccompounds (such as the structure below) having antibacterial activityand DNA gyrase inhibiting activity.

For such compounds, the relationship of the N₁ to the C₄-carbonyl isskewed. Compounds of this type are ineffective against bacteria that arequinolone resistant.

Other tricyclic analogs of the following structure are disclosed asquinolone mimics (JP 4,091,090 3/92; Interscience Conference onAntimicrobial Agents and Chemotherapy 1991, Abstract 1494).

While the ideal quinolone N₁–C₄-carbonyl relationship is maintained, theC₂ region, where substitution is undesirable, is part of a fused-ringedsystem. These compounds are not active against quinolone resistantbacteria.

WO 96/04288 describes a series of benzoheterocycles of the formulas

where X, Y, and Z are hydrogen bond acceptor and donator groups. Amongthe compounds depicted are N-hydroxy-quinazoline-2,4-diones, where R₁–R₄can represent hydroxy, amino, nitro, a variety of alkyls, esters, andamides. In all cases, the substituent on N₁ is hydrogen. None of thesubstituents R₁–R₄ are nitrogen containing heterocycles. Noantibacterial activity is disclosed for these compounds.

U.S. Pat. No. 5,155,110 describesN₁-aryl-N-hydroxy-quinazoline-2,4-diones of the formula

where R may be halo, cyano, hydroxy, alkoxy, and substituted amino.Amino heterocycles are not included in R, and no antibacterial activityis reported for such compounds.

Compounds taught in International Publication No. WO 95/19346 as AMPA,NMDA, and kinase receptor antagonists have the formula

where R substituents are defined as alkyl or phenyl, and R₁ and R₂ aredefined as H, alkyl, alkoxy, alkenyl, halogen, NO₂, (un)substituted NH₂,CN, etc. Again, no antibacterial activity is disclosed for thesecompounds.

Kornet and coworkers (Kornet M. J. et al., J. Heterocyl. Chem., 1984;21:1533–1535) disclosed anticonvulsant compounds having the formula

where R is defined as H, Me, or Cl; R₁ and R₂ as H or Me; and R₃ as Meor t-butyl. Alternatively, R₂ and R₃, together with the nitrogen atom towhich they are attached, can form a heterocyclic ring such aspiperidinyl, morpholinyl, etc. These compounds are not reported to haveantibacterial activity.

A number of publications teach compounds having diuretic and sedativeactivities and with the generic structure as follows (ES 80/489675, JP80/33323, BE 80/199792, FR 78/33438, JP 70/97932; Baronnet R.,Callendret R., Blanchard L., Foussard-Blanpin O., Bretaudeau J., Eur. J.Med.-Chim. Ther., 1983; 18:241–247).

These are compounds in which NR₁R₂ can form a heterocycle, or R₁ and R₂independently can represent H or a small alkyl. R₃ and R₄ can representH, halogen, sulphonamide, alkyl, or alkoxy. No antibacterial activity isreported for these compounds.

International Publication No. WO 99/21840 describes3-hydroxy-quinazoline-2,4-diones as antibacterial agents.

Compounds of this type are quinolone mimics where the 3-positionexocyclic carboxylic acid of the quinolones is replaced by an oxo at the2-position and a hydroxy at the N-3-position. Compounds of this type aredesigned to keep an all-planar relationship and to have the N—OH remainacidic, as in the quinolone CO₂H (Chu, Drugs Exptl. Clin. Res., 1990;16:215). These compounds inhibit DNA gyrase and topoisomerase IV, anddemonstrate antibacterial activity in vitro. However, such compounds arenot effective against quinolone resistant bacteria.

The need continues to find new antibacterial agents that have thepotency of the quinolones, but which are active against quinoloneresistant bacterial strains. The present invention provides suchcompounds, which are characterized as 3-aminoquinazolin-2,4-diones. Anobject of this invention is to provide these new compounds, and a methodfor treating bacterial infections in mammals by administering thesecompounds.

SUMMARY OF THE INVENTION

The present invention provides 3-aminoquinazolin-2,4-diones havingantibacterial activity. The compounds inhibit DNA gyrase, but are notcross-resistant with quinolone mutants that are no longer sensitive toagents such as ciprofloxacin.

The invention provides compounds of Formula I

or a pharmaceutically acceptable salt thereof wherein:

-   R₁ and R₃ independently are H,    -   C₁–C₁₂ alkyl and substituted alkyl,    -   C₂–C₁₂ alkenyl and substituted alkenyl,    -   C₂–C₁₂ alkynyl and substituted alkynyl,    -   C₃–C₁₂ cycloalkyl and substituted cycloalkyl,    -   aryl and substituted aryl,    -   heterocyclic and substituted heterocyclic,    -   or heteroaryl and substituted heteroaryl;-   R₅, R₆, and R₈ independently are H,    -   (O)_(n)C₁–C₁₂ alkyl and substituted alkyl;    -   (O)_(n)C₂–C₁₂ alkenyl and substituted alkenyl;    -   (O)_(n)C₂–C₁₂ alkynyl and substituted alkynyl;    -   halo,    -   NO₂,    -   CN,    -   NR′R″ wherein n is 0 or 1;-   R′ and R″ independently are H,    -   C₁–C₁₂ alkyl and substituted alkyl,    -   C₂–C₁₂ alkenyl and substituted alkenyl,    -   C₂–C₁₂ alkynyl and substituted alkynyl,    -   CO—C₁–C₁₂ alkyl and substituted alkyl,    -   or R′ and R″ taken together with the nitrogen to which they are        attached form a 3- to 7-membered ring containing from 1 to 3        heteroatoms selected from N, O, and S, said ring being        unsubstituted or substituted with up to 4 substituent groups;-   R₁ and R₈ can be taken together with the atoms to which they are    attached to form a cyclic ring having from 1 to 3 heteroatoms    selected from N, O, and S, and optionally substituted by R′ and R″;-   R₇ is hydrogen,    -   C₁–C₁₂ alkyl and substituted alkyl,    -   C₂–C₁₂ alkenyl and substituted alkenyl,    -   C₂–C₁₂ alkynyl and substituted alkynyl,    -   halo,    -   NO₂,    -   CN,    -   NR′R″,    -   COOR′,    -   aryl,    -   fused aryl,    -   heterocyclic,    -   fused heterocyclic,    -   bicyclic heterocyclic, or    -   spiro heterocyclic wherein all ring groups can be substituted;-   J and K independently are C or N, provided that when J or K is N, R₆    or R₈ is absent at that position.

R₇ is referred to herein as the “side chain” of the3-aminoquinazolin-2,4-dione nucleus. The R₇ side chain can be any groupknown in the quinolone art as a suitable substituent at the 7-positionof the quinolone ring.

Preferred compounds of this invention have Formula II

wherein R₁, R₃, R₆, R₇, and R₈ are as defined above.

Further preferred compounds have Formula III

wherein R₃, R₆, R₇, and R′ are as defined above.

Another preferred group of compounds have Formula IV

wherein R₁, R₃, R₆, and R₇ are as defined above.

The most preferred compounds of this invention have Formula V

wherein R₁, R₃, R₆, R₈, R′, and R″ are as defined above. An especiallypreferred embodiment are compounds of Formula V wherein R′ and R″ aretaken together with the nitrogen to which they are attached to completea ring which is optionally substituted with groups such as alkyl andsubstituted alkyl, and amino, alkylamino, dialkylamino, and aryl amino.

A further preferred group of compounds have Formula VI

wherein R₁, R₃, R₆, R′, and R″ are as defined above.

Still another preferred group of invention compounds are those ofFormula VII

wherein R₁, R₃, R₇, and R₈ are as defined above.

Especially preferred compounds provided by the invention are:

-   3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-piperazin-1-yl-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-2,4-dione;-   3-Amino-7-((S)-3-N-methylaminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-8-chloro-1-(2,4-difluoroanilino)-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-6,8-difluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-5,6,8-trifluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   7-((S)-3-Aminopyrrolidin-1-yl)-1-cyclopropyl-3,5-diamino-6,8-difluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminoethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-6-fluoro-1-isopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolin-1-yl)-1-sec-butyl-8-chloro-6-fluoro-1H-quinazoline-2,4-dione,-   3-Amino-7-[3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-aminopyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-6-chloro-1-cyclopropyl-8-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropylmethyl-8-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropylmethyl-8-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-ethyl-8-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-1-ethyl-6-fluoro-7-[(R)-3-(1-amino-1-methylethyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;-   3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-carbonitrile;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   5-Amino-9-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione;-   5-Amino-9-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-fluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione;-   2-Amino-8-((S)-3-aminopyrrolidin-1-yl)-9-fluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione;-   2-Amino-8-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-9-fluoro-5-methyl-6,7-dihydro-5H-pyrido    [3,2,1-ij]quinazoline-1,3-dione;-   3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-c]pyridin-2-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-b]pyridin-2-yl)-1H-pyrido    [2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   trans-3-Amino-7-(3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[(R)-3-((R)-1-methylamino-ethyl)pyrrolidin-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-aminopropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;-   3-Amino-7-[7-(1-aminoethyl)-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidine-3-carboxylic    acid amide;-   3-Amino-[7-trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-{3-[(2,2,2-trifluoro-ethylamino)methyl]pyrrolidin-1-yl}-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-benzylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyimino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;-   3-Amino-7-[trans-3-amino-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[(R)-3-(S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;-   3-Amino-7-(trans-3-amino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[trans-3-amino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;-   3-Amino-7-(3-aminomethylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[3-(isopropylamino-methyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-6,8-dichloro-1-cyclopropyl-1H-quinazoline-2,4-dione;-   N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;-   3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(1-aminoethyl)-3-methoxypyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(1-aminoethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-methoxymethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3    (-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-ethyl-6-fluoro-1H-quinazoline-2,4-dione;-   1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylic    acid trifluoroacetate;-   1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylic    acid trifluoroacetate;-   3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(octahydropyrrolo[3,4-b]pyridin-6-yl)-1H-quinazoline-2,4-dione;-   3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylmorpholin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1yl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1yl-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin-1-yl]-8-methyl-1    H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;-   (S)-1-[(R)-1-(3-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   cis-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   trans-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(1-amino-5-azaspiro    [2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-aminoethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-7-[3-(isopropylaminomethyl)    pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)-octahydropyrrolo[3,4-b]pyridin-6-yl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-amino-4-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminoazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;    3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;-   {(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;-   3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione,-   3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methooxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methooxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-   -Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;-   {(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;-   {(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;-   {2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;-   3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido    [4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido    [4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;-   3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione,-   3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido    [3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1    amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1    cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;-   {2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;-   3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-6H-quinazoline-2,4-dione;-   3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-1H-quinazolin-2,4-dione;-   3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione-   3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-5,8-dimethyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-5-methyl-1H-quinazoline-2,4-dione;-   3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-8-methoxy-5-methyl-1H-quinazoline-2,4-dione;-   3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dione;    and-   3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-5-methyl-1H-quinazoline-2,4-dione.

A further embodiment of the invention is a pharmaceutical compositioncomprising a compound of Formula I together with an excipient, carrier,or diluent. Preferred compositions will have a compound of Formulas II,III, IV, V, VI, or VII mixed with an excipient, carrier, or diluent.

Still another embodiment of the invention is a method of treatingbacterial infections in mammals comprising administering anantibacterial effective amount of a compound of Formula I. Preferredmethods comprise administering a compound of Formulas II, III, IV, V,VI, or VII.

Another embodiment is a method of preventing or eliminating bacterialgrowth on surfaces comprising applying to the surface an antibacteriallyeffective amount of a compound of Formulas I–VII.

DETAILED DESCRIPTION

All references cited herein, including patents, are incorporated hereinby reference.

The terms used in this specification and the appended claims have thefollowing meanings. The term “halo” means chloro, bromo, fluoro, andiodo.

The term “alkyl” means a straight or branched hydrocarbon radical havingfrom 1 to 12 carbon atoms and includes, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, 2-isopropylheptyl, 3-n-butyloctyl, n-nonyl,n-decyl, undecyl, and dodecyl.

Preferred alkyl groups are C₁–C₆ alkyl such as methyl, isopropyl,neopentyl, and 1-methylpentyl.

The term “C₂–C₁₂ alkenyl” means a straight or branched hydrocarbonradical having from 1 to 3 double bonds. Examples include ethenyl,2-propen-1-yl, 1,3-butadien-1-yl, 3-hexen-1-yl, 5-octen-2-yl,2-isopropyl-3,5-octadien-1-yl, cis-3-hexen-1-yl, andtrans-2-hepten-1-yl. Preferred alkenyl groups include C₂–C₆ alkenylssuch as ethenyl, 2-propen-1-yl, 2-buten-1-yl, and 3-penten-1-yl.

The term “C₂–C₁₂ alkynyl” means a straight or branched hydrocarbonradical having from 1 to 3 triple-bonds. Examples include ethynyl,propynyl, 3-butyn-1-yl, 4-hexyn-1-yl, 5-octyn-3-yl, 4,6-octadiyn-1-yl,4-decyn-1-yl, and 1,1-dimethyl-5-decyn-1-yl. Preferred alkynyl groupsare C₂–C₆ alkynyls such as ethynyl, propynyl, 3-butyn-1-yl, and5-hexyn-1-yl.

The alkyl, alkenyl, and alkynyl groups can be substituted with 1 to 3groups selected from halo, hydroxy, cyano, C₁–C₆ alkoxy, nitro, amino,C₁–C₆ alkylamino, di-C₁–C₆ alkylamino, carboxy, C₁–C₆ alkoxycarbonyl,aminocarbonyl, halo-dihalo and trihalomethyl, thiol, alkylsulfanyl,alkylsulfinyl, and aminosulfonyl. Examples of substituted alkyl groupsinclude fluoromethyl, tribromomethyl, hydroxymethyl, 3-methoxypropyl,3-carboxypentyl, 3,5-dibromo-6-aminocarbonyldecyl, and4-ethylsulfinyloctyl. Examples of substituted alkenyl groups include2-bromoethenyl, 1-amino-2-propen-1-yl, 3-hydroxypent-2-en-1-yl,4-methoxycarbonyl-hex-2-en-1-yl, and2-nitro-3-bromo-4-iodo-oct-5-en-1-yl. Typical substituted alkynyl groupsinclude 2-hydroxyethynyl, 3-dimethylamino-hex-5-yn-1-yl, and2-cyano-hept-3-yn-1-yl.

The term “cycloalkyl” means a hydrocarbon ring which contains from 3 to12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, decalinyl, norpinanyl, and adamantyl. Where possible, thecycloalkyl group may contain double bonds, for example,3-cyclohexen-1-yl. The cycloalkyl ring may be unsubstituted orsubstituted by 1 to 3 substituents selected from alkyl, alkoxy,thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyl anddialkylamino, formyl, carboxyl, CN, —NH—CO—R′, —CO—NHR′—, —CO₂R′, —COR′,aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl are as definedherein. Examples of substituted cycloalkyl groups includefluorocyclopropyl, 2-iodocyclobutyl, 2,3-dimethylcyclopentyl,2,2-dimethoxycyclohexyl, and 3-phenylcyclopentyl.

The term “heterocyclic” means a cyclic or fused bicyclic or polycyclicring system having from 3 to 12 ring atoms, with from 1 to 5 beingheteroatoms selected from N, O, and S. The heterocyclic groups can besubstituted with 1 to 3 of the substituents listed above for thecycloalkyl groups. Examples of heterocyclic groups include cyclic ethers(oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, andsubstituted cyclic ethers, wherein the substituents are those describedabove for the alkyl and cycloalkyl groups. Typical substituted cyclicethers include propyleneoxide, phenyloxirane (styrene oxide),cis-2-butene-oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofuran,2,6-dimethyl-1,4-dioxane, and the like. Heterocycles containing nitrogenare groups such as pyrrolidine, piperidine, piperazine,tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as3-aminopyrrolidine, 4-methylpiperazin-1-yl, and the like. Typical sulfurcontaining heterocycles include tetrahydrothiophene,dihydro-1,3-dithiol-2-yl, and hexahydrothiepin-4-yl. Other commonlyemployed heterocycles include dihydro-oxathiol-4-yl,tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl,tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl,morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl,octahydrobenzofuranyl, octahydrobenzimidazolyl, andoctahydrobenzothiazolyl. For heterocycles containing sulfur, theoxidized sulfur heterocycles containing SO or SO₂ groups are alsoincluded. Examples include the sulfoxide and sulfone forms oftetrahydrothiophene.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms, and being unsubstituted or substituted with up to 3of the substituent groups recited above for alkyl, alkenyl, and alkynyl.Examples of aryl groups include phenyl, 2,6-dichlorophenyl,3-methoxyphenyl, naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl,phenanthrenyl, benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and4′-bromobiphenyl.

The term “heteroaryl” means an aromatic cyclic or polycyclic ring systemhaving from 1 to 4 heteroatoms selected from N, O, and S. Typicalheteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-,or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl,tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl,2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-,5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-,5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-,5-, 6-, or 7-benzothiazolyl. The heteroaryl groups may be unsubstitutedor substituted by 1 to 3 substituents selected from those describedabove for alkyl, alkenyl, and alkynyl, for example, cyanothienyl andformylpyrrolyl.

Preferred aromatic fused heterocyclic rings of from 8 to 10 atomsinclude but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

Preferred compounds of the invention have Formula I wherein R₇ is aheterocyclic or heteroaryl group such as those described above. Suchheterocyclic and heteroaryl groups will be referred to hereingenerically as

Further examples of typical heterocycles, fused heterocycles, andheteroaryl groups that are preferred as R₇ substituents are listed belowin Table A.

TABLE A

The foregoing groups are especially preferred as R₇ side chains on thequinazoline ring system. The heterocycles and heteroaryl groups such asthose depicted above are known in the quinolone art and are prepared byliterature methods such as J. Med. Chem., 1992;35:1764; J. Med. Chem.,1996;39:3070; Synlett., 1996:1097; and J. Med. Chem., 1986;29:445. Anyof the primary or secondary amines shown as substituents on theheteroaryl or heterocyclic groups may be substituted by alkyl, such asmethyl, ethyl, isopropyl, and the like.

Some of the compounds of Formula I are capable of formingpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention and areprepared by art recognized methods. For example, an acid addition saltis prepared by contacting the free base form of the invention compoundwith a sufficient amount of the desired acid to produce the salt in theconventional manner. Pharmaceutically acceptable acid addition salts ofthe compounds of Formula I include salts derived from inorganic acidssuch as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic,hydriodic, hydrofluoric, phosphorous, and the like, as well as the saltsderived from organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, acetate,trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate,succinate suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzensulfonate, toluenesulfonate, phenylacetate, citrate, lactate,tartrate, methanesulfonate, and the like. Also contemplated are salts ofamino acids such as arginate and the like, as well as gluconate andgalacturonate. All such salts are readily prepared, for example asdescribed by Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 1977;66:1–19.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines,when compounds of Formula I have an acidic group such as carboxy. Thebase addition salts of acidic invention compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. Typical basesinclude sodium hydroxide, calcium oxide, diethylamine, and pyridine.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., supra., 1977).

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers. Each center may exist in the R or S configuration. Thepresent invention includes all diastereomeric, enantiomeric, andepimeric forms, as well as the appropriate mixtures thereof.Additionally, the compounds of the present invention may exist asgeometric isomers. The present invention includes all cis, trans, syn,anti, entgegen (E), and zusammen (Z) isomers, as well as the mixturesthereof.

Structures of representative compounds of the invention are shown belowin Table 1.

TABLE 1

The compounds of Formula I can be prepared utilizing standard syntheticmethodology well-known to those skilled in the art of organic chemistry.Many of the compounds have reactive functional groups that generallyneed to be derivatized with a protecting group in order to avoidunwanted side reactions. For example, functional groups such asalcohols, acid groups, and amines generally are protected while areaction is carried out at a different site in the molecule, and thenthe protecting group is subsequently removed following the desiredchemical transformation. The use of such protecting groups is standardin organic chemistry synthesis, as described, for example, in T. W.Green and P. G. Wuts, Protective Groups in Organic Synthesis, 2^(nd)edition, New York City: John Wiley & Sons, 1991. Thus, for example,protecting groups such as the following may be utilized to protectsuitable amino, hydroxyl, and other groups of related reactivity:carboxylic acyl groups, such as formyl, acetyl, trifluoroacetyl;alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl (BOC),β, β, β-trichloroethoxycarbonyl (TCEC), β-iodoethoxycarbonyl;aryloxycarbonyl groups, such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, suchas trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such astrityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized.The protecting group may be removed, after completion of the syntheticreaction of interest, by procedures known to those skilled in the art.For example, a BOC group may be removed by acidolysis, a trityl group byacidolysis or hydrogenolysis, TBDMS by treatment with fluoride ions, andTCEC by treatment with zinc.

Illustrations of typical preparations of compounds of the presentinvention having Formula I are shown in Schemes 1–22. Typicalheterocyclic and aromatic side chains defined by R₇ in Formula I areprepared as described in Schemes A1–A8. All of the3-aminoquinazoline-2,4-diones of the invention may be prepared fromappropriately substituted benzoic acid starting materials. Protectinggroups (referred to in the schemes as “Pro”) may be used whenappropriate throughout many of the schemes. Although specifically notedin certain schemes, the appropriate use and choice of protecting groupsis well-known by those skilled in the art, and is not limited to thespecific illustrations shown below. It should also be understood thatsuch protecting groups not only serve to protect chemically reactivesites, but also to enhance solubility or otherwise change physicalproperties of the underlying invention compound. A number of generalreactions such as oxidations and reductions are not shown in detail inthe schemes, but can be carried out by standard methods well-known tothose skilled in the art. In general, the starting materials used in thefollowing schemes are obtained from commercial sources, or are readilyprepared by standard methods. All cited published articles, patents,books, and the like are incorporated herein by reference.

As shown in Scheme 1, a difluoro substituted benzoic acid is reactedwith oxalyl chloride or an equivalent acylating reagent (such as an acidanhydride), and the acid halide or anhydride is reacted with an alcohol(ZOH) to afford the respective ester (Z is C₁–C₆ alkyl such as methyl,ethyl, isopropyl, etc.). The ester is reacted with an amine, forexample, a heterocyclic amine, to produce the desired 4-heterocyclicphenyl derivative. Alternatively, carbocycles and aryls may also beintroduced at this 4-position using palladium catalyzed couplings of tinor boronate carbocycles and aryls, with starting materials containing aBr, I, or triflate at the 4-position as described by Suzuki A., PureAppl. Chem., 1994; 66(2):213–222 and Stille J. K., Angew. Chem. 1986;98(6):504–519.

Reaction of the 2-fluoro benzoic acid analog with a primary amine R₁NH₂affords the corresponding 2-amino benzoic acid ester. The ester group isreadily hydrolyzed by reaction with an acid such as hydrochloric acid ora base such as sodium hydroxide to give the correspondingpolysubstituted 2-amino benzoic acid. The acid is then coupled to anappropriately protected hydrazine to provide the corresponding amide,which in turn is cyclized to generate the quinazoline-2,4-dione bytreatment with, for example, phosgene. At this point, the protectinggroup may be removed to give the free amine A of Formula I, which canrepresent a final product of the invention, and which can be furtherderivatized, if desired, for instance by alkylation with R₃Cl.

Alternatively, the quinazoline-2,4-dione may also be metallated at lowtemperatures with bases such as, for example, NaH, KH, and lithiumdiisopropylamine, and then alkylated or acylated to provide thecorresponding N-protected-mono-substituted (R₃) amine. The protectinggroup (Pro) of the N-protected-mono-substituted amine is removed byconventional methods such as hydrogenation, treatment with acid or base,or metal catalysis to afford invention compound C.

If R₅ is a leaving group such as F, it is activated towards displacementwith a nucleophile HY-Pro′ where Y is N or O and Pro′ is a protectinggroup such as trimethylsilyl. Other R₅ groups such as chlorine, bromine,or sulfonyl are also good leaving groups. The displacement generally iscarried out in a solvent such as ethanol, DMSO, DMF, THF, and at atemperature of about 0° C. to 120° C.

The protecting groups (Pro) may be selectively removed by hydrogenation,acid or base treatment, metal catalysis, or such other standard methods.When Pro is benzyl, the benzyl may be removed with Pd/C and hydrogen. At-butyl carbamate group may be removed by alcoholic HCl, TFA, or TFA indichloromethane, ethyl acetate or diethyl ether. Allylic carbamates maybe removed by PhSiH₃ and Pd catalyst. Solvents such as alcohol, THF,alcohol/THF, alcohol/THF/DMF, diethyl ether, etc. are generally employedin such protecting group cleavage reactions.

In Scheme 2, an ortho-aminobenzoic acid is utilized as the startingmaterial, and is alkylated on the amino group. For example, when R₁ iscyclopropyl, the alkylation is carried out according to the method ofGillaspy (Tetrahedon Letters, 1995:7399) to provide the cyclopropylamine. When R₁ is phenyl or substituted phenyl, the respective amine isprepared from the ortho-fluorobenzoic acid using a base, such as,lithium diisopropylamide or Li-hexamethyl disilazide, and theappropriate aryl amine (R₁NH₂). When R₁ is any alkyl group, such ast-butyl or isopropyl, the R₁ can be introduced by reacting the amine andortho halo benzoic acid with a Cu catalyst such as copper, bronze, orcupric acetate in the presence of a base such as potassium acetate,triethylamine, or pyridine.

The resulting R₁-substituted amino benzoic acid is then coupled to anappropriately protected hydrazine to provide the corresponding benzamideusing methods described in the literature. The corresponding amide canbe further reacted, if R₇ is a leaving group such as fluoro, withvarious heterocyclic amines (e.g., piperidine or pyrrolidine) to formthe desired 4-heterocyclic benzamide derivative. Alternatively,carbocycles and aryls (e.g., cyclobutyl or phenyl) may also beintroduced at this 4-position using palladium catalyzed couplings of tinor boronate carbocycles and aryls, if the starting material contains aBr, I, or triflate at the 4-position.

The 4-substituted benzamide derivative is then cyclized to generate thequinazoline-2,4-dione by reaction with carbonyldiimidazole (CDI),phosgene, triphosgene or the like in ethereal solvents such as diethylether, chlorinated hydrocarbons such as dichloromethane, or aromatichydrocarbons such as toluene, in the presence of a base such astriethylamine or NaHCO₃.

Alternatively, the corresponding amide is first cyclized and then the R₇halo group is displaced by reaction with a carbocyclic amine

to afford the same product. Deprotection by conventional methodsprovides the invention compound A.

Scheme 3 illustrates alkylation at the 1-position of a3-aminoquinazolin-2,4-dione to provide invention compounds wherein R₁ isalkyl. A 2-aminobenzoic acid is reacted with an N,N-diprotectedhydrazine such as dibenzyl hydrazine (H₂N—NBn₂) to provide thecorresponding N-protected amide. This intermediate can then be reactedwith phosgene or phosgene/base in an ethereal solvent, or with aphosgene equivalent such as triphosgene in a chlorinated hydrocarbonsuch as dichloromethane, to give the quinazoline-2,4-dione. Thealkylation of the quinazoline-2,4-dione to provide a1-alkylated-quinazoline-2,4-dione is accomplished by reaction with analkyl halide as described by Bouzard, supra., 1990. Typically, suchreactions are carried out in THF, ether, DMSO, an alkanol, or DMF, andin the presence of a base. Typical alkyl halides (R₁X where X is halo)include ethyl iodide, ethyl bromide, cyclopropyl iodide, n-decylbromide, and the like. Typical bases include sodium hydride, potassiumcarbonate, and the like. Conversion of the1-alkylated-quinazoline-2,4-dione to other invention compounds (andremoval of protecting groups such as benzyl Bn) can be carried outaccording to Scheme 1, for example, to give the corresponding 1-alkyl(R₁=alkyl) 3-amino (NH₂) compounds such as A.

Displacement of leaving groups located at the 7-position of thequinazolin (e.g., R₇=halo) as shown in Schemes 1 and 2 is not limited tonitrogen heterocycles. Other nucleophiles (Nu) such as CH₃O—, N₃—,R′R″NH, R′—NH₂, and R′S— (where R′ and R″ are defined above) alsodisplace a leaving group such as F, Cl, or NO₂ at the 7-position asshown in Scheme 4. When the leaving group is a triflate or higherhalide, organo tin reagents or organoboronates may be used withpalladium catalysts to deliver a carbon nucleophile. The methodologyshown in Scheme 4 follows that of Stille et al., Angew. Chem. Int. Ed.Eng., 1986; 25:508 and is exemplified by Mitchell (Synthesis, 1992:803).

All of the chemistry depicted and described in Schemes 1 to 4 isapplicable to make compounds of Formula I wherein J and K both arecarbon, or where one or both of J and K are N. When either J or K isnitrogen, the displacement reactions described above is even more facilethan when J and K are carbon.

Compounds of the invention where J and/or K of Formula I are nitrogenmay be prepared by the Schemes 1, 2, 3, and 4, or by routes which takeadvantage of the activation of leaving groups ortho and para to the Jand/or K nitrogen atom. Such routes will systematically introduce R₇ andR₁ groups as desired. This methodology also applies to cases in FormulaI where K—R₈ is C—H or C—F and J—R₆ is C—F. Such systematicsubstitutions are illustrated in Scheme 5. For example, a pyridine amidehas leaving groups such as halo on both sides of the nitrogen. Suchgroups are generally chlorine, but fluorine, alkylthiol, and sulfoxidessuch as methyl sulfoxides are also good leaving groups for suchcompounds. These leaving groups may be sequentially displaced based onreactivity. In Scheme 5, where J=N or J—R₆=CF, the 4-chloro (para to theaminocarbonyl group) is displaced preferentially (relative to the2-chloro group) using a nucleophilic amine such as diethylamine,pyrrolidine, methylpiperazine, and the like to give the correspondingamino substituted analog. This analog is then reacted with R₁NH₂ todisplace the second leaving group (e.g., the 2-chloro group). Theresulting 2,6-disubstituted-pyridylamide is then reacted with CDI,phosgene, or other phosgene equivalents to form the cyclized quinazolineproduct. Amination at the 3-position NH is achieved by reaction with anynumber of aminating reagents such as ammonia and N-alkylamines, forexample, as described by Kloetzer (Sci. Pharm., 1984; 52:46–50) to givethe corresponding invention compound.

Tricyclic compounds (i.e., where R₁ and R₈ in Formula I are takentogether with the atoms to which they are attached to form a ring) canbe prepared according to Schemes 6 and 7. Schemes 6 and 7 differ in theintroduction of the R₁ substitutions in Structures B and C whereinR₁=R₁′ and R₁ is as defined above for Formula I and R₁′ is alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and the like. In Scheme6, the ortho-fluoro nitro compound (other leaving groups such aschlorine, bromine, and sulfonyl may also be employed in place of fluoro)is displaced by the α-nucleophile substituted ester (where Q is anucleophile Nu such as methyl or methoxy). The nitro group is thenreduced using, for example, Raney Ni, H₂ over Pd/C, or an active metalin acid such as iron or tin in HCl or acetic acid. The newly formedamine readily cyclizes with the ester (other acid analogs may beemployed such as thioesters, amides, and the like). The cyclized productis then reduced with hydride reducing agents such as LiAlH₄ and the liketo produce the dihydroquinoline derivative, which in turn is reactedwith chloral hydrate and then an acid to form the dione ring. The dionering is subsequently opened using, for example, sodium hydroxide andhydrogen peroxide to give the benzoic acid. The 3-aminoquinazolinedionering is then prepared using the chemistry described in Schemes 2, 3, or5 to give the invention compound B, where R₃′ is alkyl, alkenyl,cycloalkyl, aryl, and heteroaryl.

In a similar series of reactions depicted in Scheme 7, the ortho-fluoronitro compound is reacted with an α-nucleophile substituted ketone, andthe resulting product is likewise reduced. In this sequence, theresulting aniline forms a cyclic imine, which is further reduced with H₂on Pd/C or by chemical hydride reducing agents such as sodiumborohydride or sodium cyanoborohydride to give the dihydroquinoline.Such reductive aminations are well-known in the art and are typicallyperformed in THF, alcohol, water alcohol mixtures, or in water DMFmixtures. The remaining steps to produce C follow those of Scheme 6.When the C-7 substituent is a leaving group (e.g., R₇=halo), compounds Band C may be further reacted with nucleophiles (such as pyrrolidine orpiperidine) to give compounds of Formula I as in the previous schemes.

In Scheme 8, the target tricylic compounds as C are prepared in aslightly different manner. In this case, the nucleophile Q (such ashydroxymethyl) is attached to the phenyl ring of the starting aniline,and a leaving group L (such as halo) is attached alpha to the ketonereactant. The nucleophile may be activated with bases such as sodiumhydride or potassium hydride, triethylamine or1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), or sodium, potassium, orcesium carbonate to displace the leaving group L. In this sequence, theresulting aniline forms a cyclic imine, which is further reduced with H₂on Pd/C or by chemical hydride reducing agents such as sodiumborohydride or sodium cyanoborohydride to give a dihydroquinoline. Suchreductive aminations are well-known in the art and are typicallyperformed in THF, alcohol, water alcohol mixtures, or in water DMFmixtures. The dihydroquinoline intermediate is reacted with chloralhydrate, and then an acid to form the dione ring. The dione ring issubsequently opened by reaction with a base, for example sodiumhydroxide and hydrogen peroxide, to give the benzoic acid. The3-aminoquinazolindione ring is then prepared by first forming an esteron the benzoic acid as in Scheme 2, followed by reaction of the benzoicacid ester with chlorosulfonylisocyanate or the like at temperatures of0° C. and below, followed by treatment with a base such as triethylamineor diisopropylethylamine. Amination can then be carried out in the samemanner as described in Scheme 5 to provide compounds of structure C.When R₇ is a leaving group such as Cl or F, the invention compounds ofstructures B (in Scheme 6) and D (in Scheme 8) can be prepared bycoupling to the R₇ side chain, e.g., various heterocyclic amines

to produce the desired derivatives. Alternatively, carbocycles and arylsmay also be introduced as R₇ side chains using palladium catalyzedcouplings with tin or bornate carbocycles and aryls, for example when R₇is a Br, I, or triflate.

It should be noted from Schemes 6, 7, and 8 that R₁′ and R₃′ will formchiral centers, giving R and S enantiomers and diastereomers. Suchenantiomers or diastereomers may be separated, if desired, at any stageby chiral HPLC, or by other conventional resolution techniques.Resolution of the precursor benzoic acid may also be accomplished byfractional crystallization using mandelic acid, tartaric acid, or otherchiral, optically pure acid bearing resolving agents. Chiral amides mayalso be prepared from the benzoic acids using chiral amines such ascamphorsulfonamide, benzylamine, or the like. The isomers can then beseparated and the chiral amide hydrolyzed as desired.

Scheme 9 illustrates synthesis of compounds of Formula I wherein one orboth of R₆ and R₈ are halo via halogenation. The halogenation is carriedout on a 2-aminobenzoic acid where one or both of R₆ and R₈ is hydrogen.If both R₆ and R₈ in the benzoic acid are H, then halogenation can beaccomplished at both positions selectively or simultaneously. Thus, forexample, chlorination at R₆ or R₈ is achieved by reaction of the benzoicacid with N-chlorosuccinamide, t-butylhypochlorite, chlorine gas, andthe like. Similarly, bromination at R₆ and R₈ can also be accomplishedby reaction of the benzoic acid with Br₂, N-bromosuccinimide, and thelike. Such halogenations are well-known in the art. Halogenationprovides the respective mono- or dihalo compound. The halogenatedbenzoic acid can be further reacted as shown in Schemes 1 and 2 toprovide the quinazoline-2,4-diones of Formula I.

In Scheme 10, compounds where R₈ is H are halogenated as described inScheme 9 to provide the corresponding 3-halo-2-aminobenzoic acid(Y=halo). This intermediate can then be diazotized by reaction of the2-amino group with sodium nitrite or t-butyl nitrite, which is thenconverted to a 2-halobenzoic acid in the presence of an appropriatesodium, potassium, or copper salt such as sodium iodide, potassiumchloride, and the like. The resulting 2,3-dihalobenzoic acid (where Xand Y both are halo) is then converted to the 3-halo-2-aminobenzoic acidby reaction with an amine R₁NH₂ in the presence of a copper catalyst.The 3-halo-2-aminobenzoic acid is converted to an amide and cyclized tothe corresponding 8-halo-3-amino-quinazolin-2,4-dione, as illustrated inScheme 2.

Compounds of Formula I wherein R₆ and/or R₈ is halo such as chloro orbromo are readily dehalogenated by reaction with metal catalysts underhydrogen pressure (Scheme 11). Suitable catalysts include the manyvariations of Pd on carbon, Raney nickel, or other reagents that arewell-known to effect such dehalogenation.

Compounds of Formula I wherein R₆ and/or R₈ are hydrogen can behalogenated to give the mono- or dihalo compound (e.g., R₆ or R₈=Cl orBr). The invention compounds are preferably prepared by firsthalogenating a benzoic acid derivative, and then cyclizing thehalogenated benzoate (Scheme 12). If both R₆ and R₈ are H, thenhalogenation can be accomplished at both positions selectively orsimultaneously. Halogenations can be carried out as described above forScheme 10. The resulting compound is then converted to the2-substituted-aminobenzoic acid as depicted in Scheme 1, which issubsequently cyclized and aminated.

Invention compounds of Formula I can also be prepared as shown in Scheme13. Substituted benzoic acids can be converted into esters (where Z isan ester forming group such as alkyl or benzyl) by a number of methodsknown by those skilled in the art. The ester is reacted with anisocyanate such as trimethylsilylisocyanate, chlorosulfanyl isocyanate,and chlorocarbonyl isocyanate, followed by treatment with a base such astriethylamine, sodium t-butoxide or the like, to provide aquinazoline-2,4-dione. The quinazoline-2,4-dione can be aminated byreaction with an aminating agent such as ammonia as described in Scheme5 to generate the corresponding 3-aminoquinazoline-2,4-dione. Thiscompound may be further reacted, when R₇ is a leaving group such asfluoro, with various heterocyclic amines. Again, carbocycles and arylsmay also be introduced at R₇ if R₇ is a Br, I, or triflate, usingpalladium catalyzed couplings of tin or boronate carbocycles and aryls.Removal of any protecting groups (Pro) by normal means providesinvention compounds such as A, as described above in Scheme 1.

Invention compounds of Formula I having a cyano substituent can beprepared as shown in Scheme 14. For example, a benzoic acid wherein R₈is hydrogen can be metallated with a strong base such as lithiumhexamethyldisilazane or lithium diisopropylamine. The resultingmetallated intermediate can then be quenched with dimethylformamide oran equivalent to provide an aldehyde. The aldehyde can be converted toan oxime by reaction with an alkoxy amine (other electrophiles such asalkyl halides, activated amides, esters and halide sources such as1,2-dichloro-tetrafluoroethane may also be employed to provide otherbenzoic acid derivatives that can be used as defined in Schemes 1, 2,13, and 15). The oxime is converted into a cyano group under thecyclization conditions required to form the quinazolinedione ring system(e.g., reaction with phosgene) as described in Schemes 1, 12, and 13.Deprotection provides invention compounds where R₈ is —CN.

Another alternative for preparing invention compounds is illustrated inScheme 15. Appropriately substituted benzoic acids can be converted intobenzamides by any number of methods as described above. A benzamide canthen be treated with oxalyl chloride in a chlorinated solvent such asdichloroethane or an equivalent to provide an isocyanate. The isocyanateis reacted with a substituted primary amine to give a benzoylsubstituted urea. This intermediate can be cyclized to form aquinazolinedione ring system by reaction with sodium hydride, potassiumhexamethyldisilazane or other non-nucleophilic bases, generally in asolvent such as tetrahydrofuran (THF)/dimethylformamide, THF with18-crown-6, THF/dioxane, THF/glyme, THF/diglyme, dimethoxyethane/tolueneor an equivalent. The quinazolinedione can then be aminated by reactionwith any number of aminating reagents as described by Kloetzer (Sci.Pharm., 1984; 52:46–50). The resulting 3-aminoquinazolinedione ringsystem can then be readily coupled with an appropriately substitutedheterocyclic amine (such as those noted above in Table A) by reaction inthe presence of a base such as triethyl amine, diisopropylethyl amine,tetramethyl guanidine, and the like in solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, sulfolane or theequivalent. Any protecting group associated with the heterocyclic amineside chain is then removed by methods known to those skilled in the artto provide invention compounds having Structure A.

Tricyclic compounds (i.e., where R₁ and R₈, together with the atoms towhich they are attached, form a carbocyclic ring in invention compoundsof Formula I) can be prepared according to Scheme 16 where a palladiummediated carbon monoxide insertion on a quinoline (X=Br, I, or triflate)under well-precedented conditions gives rise to an ester. The quinolinering can then be hydrogenated to provide a tetrahydroquinoline bystandard hydrogenation conditions. The remainder of Scheme 16 followsthat of Scheme 8 to provide invention compounds such as G, substitutedwith a displaceable substituent at R₇ (e.g., halo). These compounds maybe further reacted with nucleophiles such as amines from Table A to givecompounds of Formula I.

Compounds of Formula I where K is N may be prepared by the routes shownin Schemes 1, 2, 3, 4, and 6, or by routes such as the one illustratedin Scheme 17, which follows closely the chemistry shown in Scheme 15.The leaving groups (e.g. halo) ortho and para to the carboxyl group ofthe pyridyl starting material are highly activated. The two leavinggroups ortho to the pyridine nitrogen are generally chlorine, butfluorine, alkylthiol, and sulfoxides such as methylsulfoxide are alsogood leaving groups for such compounds. The urea intermediate readilycyclizes to the 7-halo-quinazolinedione. Amination at the 3-positiongives an invention compound that is an important intermediate due to thegood leaving group at the 7-position (R₇=halo), which is readilydisplaced by reaction with an amine

Scheme 18 illustrates the synthesis of benzoic acid starting materialsthat have a bromo for R₇. A difluoro substituted benzoic acid isconverted to an ester by first reaction with oxalyl chloride or anequivalent reagent (including acid anhydride), and the acid halide oranhydride is reacted with an alkanol to afford the respective ester(Z=methyl, ethyl, isopropyl, etc.). The ester is then reacted with4-methoxybenzylamine or an equivalent to produce the desired4-substituted benzoic acid derivative. This intermediate is reacted withtriethylsilane and trifluoroacetic acid in a chlorinated solvent such asdichloromethane or an equivalent to provide an aniline derivative.Alternatively, one skilled in the art might also employ transition metalcatalysis. The resulting aniline is then subjected to diazotization andconverted to a bromide by treatment with cuprous bromide. The ester isthen hydrolyzed by well-known methods to the desired benzoic acid, whichcan be used as a starting material as illustrated in Scheme 20 below.

In Scheme 19, 4-bromo-2-fluorobenzoic acid derivatives can beselectively chlorinated by treatment with chlorine gas in chlorosulfonicacid at a temperature of 40° C.–100° C.

Scheme 20 illustrates use of 4-bromobenzoic acids as starting materialsto make invention compounds wherein R₇ is aryl. The 4-bromobenzoic acidsare converted into benzamides by any number of methods known in the art.A benzamide is reacted with oxalyl chloride in a chlorinated solventsuch as dichloroethane or an equivalent to provide an isocyanate. Theisocyanate is reacted with a substituted primary amine to give a benzoylsubstituted urea. This intermediate can be cyclized to form aquinazolinedione ring system by reaction with sodium hydride, potassiumhexamethyldisilazane or other non-nucleophilic bases intetrahydrofuran/dimethylformamide, tetrahydrofuran with 18-crown-6,toluene/dioxane, tetrahydrofuran/glyme, tetrahydrofuran/diglyme,glyme/toluene or an equivalent. The quinazolinedione can then beaminated with a number of aminating reagents as described in Scheme 15.The resulting 3-aminoquinazolinedione ring system can then be readilycoupled with a stannane or boronic acid derivative of a substituted arylsuch as phenyl or substituted aromatic heterocycle (Ar).

Alternatively, the 3-position amine can be protected with a protectinggroup such as a tert-butyl carbamate or trifluoroacetamide. Protectinggroups of these types are well known in the art. The 3-derivatizedaminoquinazolinedione ring system can then be coupled via palladiumcatalysis with an aromatic (Ar) stannane or boronic acid.

Each of the outlined routes, upon deprotection by standard procedures,provides invention compounds of Formula I where R₇ is aryl such asphenyl or substituted phenyl, or heteroaryl such as pyridyl orsubstituted pyridyl.

Compounds of Formula I wherein R₇ is a heteroaryl group (such as thosein Table A) are alternatively prepared as illustrated in Scheme 21,where R₇ is a substituted thiazole. A 3-protected3-amino-7-bromoquinazolinedione from Scheme 20 is reacted with1-tributyl-ethoxyvinyltin in the presence of a palladium catalyst. Theresulting 7-substituted adduct is reacted with a brominating reagentsuch as n-bromosuccinimide and the like in tetrahydrofuran/H₂O toprovide an bromoketone at the quinazolinedione 7-position. Reaction ofthis intermediate with a thioamide (or thiourea) in a polar solvent suchas dimethyl formamide, dimethylacetamide, or ethanol, and at an elevatedtemperature of about 80° C. to 120° C., effects cyclization to form athiazolyl group. Deprotection by known methods can then be applied toprovide invention compounds of Formula I wherein R₇ is the heteroaryl,optionally substituted with T, which is H, alkyl, substituted alkyl,NH₂, NH-allyl and N-dialkyl.

Alternatively, 7-aromatic or heterocyclic aromatic compounds of FormulaI are prepared as shown in Scheme 22. A 4-bromo-2-fluorobenzoic acid(Schemes 18 or 19) is first esterified (Z is alkyl or benzyl), and theester is reacted with a substituted primary amine (R₁NH₂) indimethylsulfoxide (DMSO) at elevated temperature of about 100° C. toprovide an anthranilic ester. The resulting aniline is then reacted withan appropriately protected hydrazine to provide the corresponding amide,for example as described in Scheme 1. The resulting amido aniline isthen cyclized by reaction with phosgene, CDI, or the like to generatethe quinazoline-2,4-dione. The cyclization typically is carried out in asolvent, such as ethereal solvents, chlorinated hydrocarbons such aschloroform, or aromatic hydrocarbons such as toluene, and in thepresence of a base such as triethylamine or NaHCO₃. Thequinazolin-2,4-dione ring system is then further modified as describedin Scheme 20 to provide the desired 7-aryl (Ar) compound of Formula I.

As noted above, R₇ in Formula I is referred to as the “side chain” ofthe 3-aminoquinazolin-2,4-dione nucleus. The R₇ side chains are any ofthose typically found on the quinolone antibiotics. Most of the R₇ sidechain reactants that are required to make the Formula I compounds arereadily available from commercial sources. Typical R₇ side chains areshown in Table A above.

The synthesis of the R₇ side chains can be accomplished by standardsynthetic methods, for example as shown in the following schemes or asfound in the literature. Those of ordinary skill in the art will be ableto make any of the starting materials required to prepare the inventioncompounds, although most are available from commercial sources. Thefollowing schemes are provided to illustrate the synthesis of typical R₇side chain reactants.

Scheme A1 illustrates the synthesis of typical pyrrolidines, which arepreferred side chains (R₇) for invention compounds of Formula I. InScheme A1, appropriately activated enones can undergo[3+2]cycloadditions under the conditions described by Tsuge et al.(Recent advances in azomethine ylid chemistry. In: Advances inHeterocyclic Chemistry [Katritsky A., ed.] San Diego: Academic Press,231–349). These reactions are carried out in a chlorinated hydrocarbonsolvent such as dichloromethane, chloroform, or dichloroethane and thelike, and in the presence of a catalytic acid such as trifluoaceticacid, to provide substituted pyrrolidines (wherein S₁, S₂, S₃, and S₄independently are alkyl, substituted alkyl, aryl, amino, alkyl anddialkylamino). These intermediates can then be treated withhydroxylamine or any O-alkylated or arylated hydroxylamine under avariety of conditions known to those skilled in the art to provideoximated substituted pyrrolidines. The oximes are reduced to amines withlithium aluminum hydride, diisobutylaluminum hydride borane, or byselective catalytic hydrogenation. The resulting primary amines can thenbe protected using a number of methods as described in “ProtectingGroups in Organic Synthesis” by Theodora Green (supra). The benzylicpyrrolidine can then be deprotected by hydrogenation, and the resultingpyrrolidine used in the preparation of 7-cyclic amino substituted3-aminoquinazolinediones of Formula I as shown in the schemes above.

In Scheme A2, enoates (or vinylogous nitrites) may also be used in[3+2]cycloadditions to provide 3- and 4-substituted pyrrolidines. Theester (or nitrite) functionality can then be treated directly with alkyllithium reagents at low temperature (0° C.) in ether to provide S₁substituted ketones, or the ester (Z is alkyl or benzyl) can behydrolyzed under conditions usually employed by those skilled in the artto provide carboxylic acids. This intermediate can then be transformedinto an acid chloride with oxalyl chloride and catalytic dimethylformamide in solvents such as dichloromethane or chloroform or into anactivated amide (Singh J., Satyamurthi N., Aidhen I., Singh J., Prakt.Chem. [Weinheim, Ger.], 2000; 342(4):340–347). An acid chloride can beconverted into a ketone using organocopper reagents (Lipshutz B. H.,Sengupta S., Org. React. [N.Y.], 1992; 41 :135–631), and Weinreb amidescan be converted into ketones according to the methods described byWeinreb (Tetrahedron Lett., 1981; 22(39):3815–3818) using organoGrignard reagents. The resulting ketones can then be converted intopyrrolidines (optionally substituted with S₂, S₃, and S₄) as describedin Scheme A1. As noted above, pyrrolidines and substituted pyrrolidinesare preferred R₇ groups in Formula I.

In Scheme A3,3-carboxylic acid N-benzyl substituted pyrrolidines (SchemeA2) can be converted into amides by a number of methods well-known tothose who practice the art of organic synthesis. The amides can then betreated with lithium aluminum hydride in an ethereal solvent such asdiethyl ether or tetrahydrofuran or the like to provide amines that canbe protected as described in Scheme A1. Hydrogenation with palladiumcatalysis provides an appropriately substituted pyrrolidine (S₂, S₃, S₄are independently alkyl, lower alkyl, aryl, etc.).

In Scheme A4, a 3-carboxypyrrolidinone (Culbertson T. P., Domagala J.M., Nichols J. B., Priebe S., Skeean R. W., J. Med. Chem., 1987;30(10):1711–1715) can be converted into an acid chloride or Weinrebamide in the same fashion as that defined in Scheme A3. The acidchlorides are reacted with an organocopper reagent or an organo Grignardreagent (for a Weinreb amide) to provide a ketone that can bemanipulated as described in Scheme A1 to provide an appropriatelysubstituted pyrrolidine with a variety of substitutions at S₁ (alkyl,lower alkyl, substituted alkyl, aryl). The use of S-methylbenzyl (orR-methylbenzyl) as a protecting group for the pyrrolidine nitrogenallows for the separation of enantiomers and diastereomers at any stepin the reaction sequence.

In Scheme A5, carboxybenzyl protected 3-pyrrolidinone is reacted with aWittig salt in the presence of sodium hydride or an equivalent indimethylsulfoxide or any polar aprotic solvent to give an olefin. Theresulting olefin is oxidized with 3-chloroperoxybenzoic acid indichloromethane or other suitable chlorinated hydrocarbon to provide anepoxide. The epoxide is reacted with ammonium hydroxide in methanol,ethanol, dimethylformamide, dimethylacetamide or the like to generate anaminoalcohol. Methylation of the tertiary hydroxyl group can then becarried out by formation of a Schiff-base, followed by alkoxideformation with sodium hydride and treatment with iodomethane. Hydrolysisof the Schiff-base under standard conditions liberates the amine.Reaction of the amine with di-tert-butyldicarbonate in methanol,followed by hydrogenation via palladium catalysis provides R₇ sidechains (S₁ is alkyl, lower alkyl, and aryl) that can be used in thesynthesis of compounds of Formula I.

In Scheme A6, the aminoalcohol intermediate described in Scheme A5 isreacted with di-tert-butyldicarbonate in methanol to produce theN-protected intermediate. Other amine protection strategies familiar tothose skilled in the art can also be utilized. Hydrogenation underpalladium catalysis provides substituted pyrrolidine R₇ side chains thatare used in the synthesis of compounds of Formula I.

In Scheme A7, an epoxide intermediate (Scheme A5) is selectively openedwith hydrofluoric acid in pyridine, and the resulting secondary alcoholis reacted with methanesulfonylchloride, or an equivalent sulfonatingreagent, in dichloromethane or another chlorinated hydrocarbon andtriethylamine. Other appropriate bases include diisopropylethylamine,pyridine, collidine, n-methylmorpholine, and the like. The mesylate isthen displaced by reaction with sodium azide, and the azide is reducedwith Raney nickel under hydrogen pressure in methanol. Suchtransformations are well-precedented in the art. The resulting amine isthen treated with di-tert-butyldicarbonate in methanol as shown inSchemes A4–A6, and the product is hydrogenated to provide the R₇ sidechain as shown above.

The synthesis of 3-substituted piperidines is demonstrated in Scheme A8.Esterification and alkylation of 3-piperidine carboxylic acid issimultaneously accomplished by treatment with a benzylbromide in a polarsolvent such as dimethylformamide or dimethylsulfoxide and a base suchas potassium carbonate (K₂CO₃) or an equivalent. The ester is thenhydrolyzed, and the resulting carboxylic acid is converted to a methylketone by treatment with methyllithium at low temperature (0° C.). Thisintermediate is then converted to an oxime by a number of methods knownby those skilled in the art. The oxime is reduced with lithium aluminumhydride in tetrahydrofuran to provide an amine. The amine is reactedwith di-tert-butyldicarbonate in dichloromethane and triethylamine as abase. As shown in Schemes A4–A6, the product is then hydrogenated toprovide the R₇ side chain.

It should be recognized from Schemes A1–A8 that substitutions on ringsystems such as a pyrrolidine, piperazine, or piperidine ring will formchiral centers giving R and S enantiomers and diastereomers. Suchenantiomers or diastereomers may be separated, if desired, by chiralHPLC at any stage. Resolution of any of the intermediates may beperformed with techniques of fractional crystallization using mandelicacid, tartaric acid, or other chiral, optically pure acid resolvingagents. Chiral benzylic amines can be used in the preparation ofstarting materials for the above schemes, and chiral amides may also beprepared using chiral acids, such as mandelic acid and the like. Theisomers can then be separated and the chiral amine can be hydrogenated,or the chiral amide can be hydrolyzed.

The synthesis of invention compounds of Formula I is further illustratedby the following detailed examples. The examples are not to be construedas limiting the invention in scope or spirit to the specific proceduresdescribed. The starting materials and various intermediates utilized inthe following examples may be obtained from commercial sources, or arereadily prepared from commercially available organic compounds, usingwell-known synthetic methods.

EXAMPLE 1 Synthesis of Benzoates (a) 2,3,4,5-Tetrafluorobenzoic acidethyl ester

A solution of 2,3,4,5-tetrafluorobenzoic acid (4.68 g, 24.1 mmol) indichloromethane (50 mL) at 0° C. is treated with oxalyl chloride (11.5mL, 132 mmol) followed by N,N-dimethylformamide (4 drops). The mixtureis stirred at 0° C. for 5 minutes and then at room temperature for 1.5hours. The mixture is concentrated to dryness and subsequentlyco-evaporated from benzene. The resulting acid chloride is diluted withdichloromethane (50 mL), cooled to 0° C., and anhydrous ethanol (15.0mL, 256 mmol) is added dropwise. The resulting solution is stirred atroom temperature for 4.5 hours, then poured into saturated NaHCO₃ andextracted with chloroform. The combined organic extracts are washed withbrine, dried over Na₂SO₄, filtered, and concentrated under vacuum toafford the title compound (5.37 g). ¹H NMR (CDCl₃): δ 7.67–7.55 (m, 1H),4.42 (q, 2H), 1.41 (t, 3H).

(b) 2,3,4,6-Tetrafluorobenzoic acid ethyl ester

2,3,4,6-Tetrafluorobenzoic acid (4.8 g, 24.7 mmol) in dichloromethane(80 mL) is cooled to 0° C. under a nitrogen atmosphere and treated withoxalyl chloride (11.2 mL, 128 mmol) followed by anhydrousN,N-dimethylformamide (2 drops). The mixture is warmed to roomtemperature and stirred for 2 hours. The solution is co-evaporated withbenzene to yield an oil that is taken up in dichloromethane (80 mL),cooled to 0° C. under an inert atmosphere, and treated with anhydrousethanol (15 mL, 258 mmol). After 5 hours at room temperature, thesolution is poured into saturated NaHCO₃ and extracted with chloroform.The organic phase is washed with brine, dried over Na₂SO₄, filtered, andconcentrated under vacuum to provide the title compound (3.3 g). Thismaterial is used without further purification. ¹H NMR (CDCl₃): δ6.93–6.75 (m, 1H), 4.42 (q, 2H), 1.39 (t, 3H).

(c) 3-Chloro-2,4,5-trifluorobenzoic acid ethyl ester

To a solution of 3-chloro-2,4,5-trifluorobenzoic acid (Example 20, 4.90g, 23.3 mmol) in dichloromethane (50 mL) is added oxalyl chloride (5.1mL, 58.2 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, thereaction mixture is concentrated under vacuum. The resulting residue isdissolved in dichloromethane (50 mL) and treated with ethanol (10 mL,172 mmol). After 30 minutes, the reaction mixture is diluted withdichloromethane and washed with saturated NaHCO₃, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrate isconcentrated to afford the title compound (5.59 g). ¹H NMR (CDCl₃): δ7.76–7.68 (m, 1H), 4.40 (q, 2H), 1.39 (t, 3H).

(d) 2,3,4,5,6-Pentafluorobenzoic acid benzyl ester

A solution of 2,3,4,5,6-pentafluorobenzoic acid (15.25 g, 71.9 mmol),4-dimethylaminopyridine (4.4 g, 36.0 mmol) and benzyl alcohol (7.4 mL,71.5 mmol) in dichloromethane (150 mL) is cooled to 0° C. under an inertatmosphere. 1-[3-(Dimethylamino)propyl]-3-ethyl carbodiimidehydrochloride (16.7 g, 87.1 mmol) is added and the mixture stirred at 0°C. for 2 hours. The mixture is warmed to ambient temperature, stirredfor 24 hours, and then poured into brine. The mixture is extracted withchloroform and the organic phase washed with NaHCO₃, dried over Na₂SO₄,filtered and concentrated under vacuum to yield the title compound as awhite solid (16.7 g). This material is used without furtherpurification. ¹H NMR (CDCl₃): δ 7.49–7.27 (m, 5H), 5.40 (s, 2H).

(e) 2,4,5-Trifluorobenzoic acid ethyl ester

To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6 mmol) indichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol)and N,N-dimethylformamide (1 drop). After 45 minutes, the reactionmixture is concentrated under vacuum. The resulting residue is dissolvedin dichloromethane (100 mL), and to this solution is added ethanol (18mL, 310 mmol). After 30 minutes, the reaction mixture is diluted withdichloromethane and washed with saturated NaHCO₃, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrate isconcentrated to afford the title compound as an oil (12.23 g). ¹HNMR(CDCl₃): δ 7.85–7.73 (m, 1H), 7.06–6.94 (m, 1H), 4.38 (q, 2H), 1.38(t, 3H).

(f) 2,4,5-Trifluoro-3-methoxybenzoic acid ethyl ester

A solution of 2,4,5-trifluoro-3-methoxybenzoic acid (2.513 g, 12.19mmol) in dichloromethane (50 mL) at 0° C. is treated with oxalylchloride (5.4 mL, 61.9 mmol) followed by N,N-dimethylformamide (4drops). The mixture is stirred at 0° C. for 5 minutes and then at roomtemperature for 2.5 hours. The mixture is concentrated to near drynessand then co-evaporated from benzene. The resulting acid chloride isdiluted with dichloromethane (50 mL), cooled to 0° C., and thenanhydrous ethanol (7.30 mL, 124 mmol) is added dropwise. The resultingsolution is stirred at room temperature for 4.5 hours, poured intosaturated NaHCO₃ solution, and extracted with dichloromethane. Thecombined organic extracts are washed with brine, dried over Na₂SO₄,filtered, and concentrated under vacuum to afford the title compound asa light yellow liquid (2.82 g). ¹H NMR (CDCl₃): δ 7.47 (ddd, 1H), 4.39(q, 2H), 4.05 (s, 3H), 1.40 (t, 3H).

(g) 2,3,4-Trifluorobenzoic acid ethyl ester

To a solution of 2,3,4-trifluorobenzoic acid (10.85 g, 61.6 mmol) indichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol)and N,N-dimethylformamide (3 drops). After 45 minutes, the reactionmixture is concentrated under vacuum. The resulting residue is dissolvedin dichloromethane (100 mL) and to this solution is added ethanol (18mL, 310 mmol). After 30 minutes, the reaction mixture is diluted withdichloromethane and washed with saturated NaHCO₃, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrate isconcentrated to afford the title compound as an oil (12.23 g). ¹H NMR(CDCl₃): δ 7.93–7.67 (m, 1H), 7.09–6.96 (m, 1H), 4.39 (q, 2H), 1.40 (t,3H).

(h) 2,3,4-Trifluoro-5-methoxybenzoic acid ethyl ester

A solution of 2,3,4-trifluoro-5-methoxybenzoic acid (Hayashi et al.,Bull. Chem. Soc. Jap., 1972; 45(9):2909–2914, 3.443 g, 16.7 mmol) indichloromethane (100 mL) at 0° C. is treated with oxalyl chloride (7 mL,80 mmol) followed by N,N-dimethylformamide (4 drops). The mixture isstirred at room temperature for 3.5 hours, concentrated to near dryness,and co-evaporated with benzene. The acid chloride is then diluted withdichloromethane, cooled to 0° C., and treated with absolute ethanol (10mL, 170 mmol). The resulting solution is stirred at room temperature for20 hours, poured into saturated NaHCO₃ solution, and extracted withdichloromethane. The organic extracts are washed with brine, dried overNa₂SO₄, filtered, and concentrated under vacuum to afford the titlecompound (3.785 g). ¹H NMR (200 MHz, CDCl₃): δ 7.36–7.29 (m, 1H), 4.42(q, 2H), 3.93 (s, 3H), 1.44 (t, 3H).

(i) 2,4,5-Trifluoro-3-methylbenzoic acid ethyl ester

A solution of 3-methyl-2,4,5-trifluorobenzoic acid (Shimizu T., Asai T.,Kumai S., Jpn. Kokai Tokkyo Koho (1997) Japanese Appl. JP 95-219069, 4.3g, 22.6 mmol) in dichloromethane (100 mL) at 0° C. is treated withoxalyl chloride (4.2 g, 33 mmol) followed by N,N-dimethylformamide (2drops). The mixture is stirred at room temperature for 3 hours,concentrated and dried in vacuo. The acid chloride is diluted withdichloromethane, cooled to 0° C., and treated with absolute ethanol (10mL, 170 mmol). The resulting solution is stirred at room temperature for20 hours, poured into saturated NaHCO₃ solution and extracted withdichloromethane. The organic extracts are washed with brine, dried overNa₂SO₄, filtered, and concentrated under vacuum to afford the titlecompound (3.8 g). ¹H NMR (200 MHz, CDCl₃): δ 7.67–7.26 (m, 1H), 4.44 (q,2H), 2.27 (dd, 3H), 1.42 (t, 3H).

(j) 3-(Benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid ethyl ester

2,4,5-Trifluoro-3-formylbenzoic acid (Horiuchi N., Yonezawa T., ChibaK., Yoshida H., PCT Int. Appl. [1999] WO 97-JP2918), (5.70 g, 27.9mmol), triethylamine (11 mL, 78.9 mmol), O-benzylhydroxylaminehydrochloride (4.47 g, 28.0 mmol) and anhydrous tetrahydrofuran (150 mL)are stirred at room temperature for 50 hours. The mixture is poured intobrine and the pH adjusted to 5.5–6.0 using 1.0 M hydrochloric acid. Themixture is extracted with ethyl acetate. The organic phase is dried overNa₂SO₄, filtered, and concentrated in vacuo to provide3-(benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (8.63 g), which isused without further purification. ¹H NMR (200 MHz, CDCl₃): δ 9.82–9.18(bs, 1H), 8.24 (s, 1H), 7.94–7.68 (m, 1H), 7.55–7.23 (m, 5H), 5.23 (d,2H). MS (EI, M−1) m/z 308.

3-(Benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (0.117 g, 0.378mmol), 4-dimethylaminopyridine (0.023 g, 0.189 mmol), anhydrous ethanol(0.030 mL, 0.517 mmol) are mixed in dichloromethane (6 mL), cooled to 0°C., and treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.082 g, 0.427 mmol). After 2 hours at 0° C. and roomtemperature for 21 hours, the solvents are evaporated. The residue isdissolved in chloroform, washed with saturated NaHCO₃ and brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification bychromatography (1:8 ethyl acetate/hexanes) provided the title compound(0.068 g). ¹H NMR (200 MHz, CDCl₃): δ 8.27 (s, 1H), 7.87–7.66 (m, 1H),7.49–7.28 (m, 5H), 5.27 (s, 2H), 4.48–4.29 (q, 2H), 1.46–1.31 (t, 3H).

EXAMPLE 2 Synthesis of 4-Heterocyclic Benzoates

General Procedure

A mixture of 4-fluoro substituted benzoic acid ester (1 eq.),substituted pyrrolidine (1.3–2.5 eq.), and triethylamine (2–10 eq.) inN,N-dimethylacetamide or acetonitrile is heated to 50° C.–100° C. for 15to 60 hours. The solution is then concentrated to near dryness, pouredinto saturated NaHCO₃ solution, and extracted with ethyl acetate. Thecombined organic extracts are washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The resulting residue is purifiedby column chromatography (ethyl acetate/hexanes) to afford4-pyrrolidinyl substituted benzoic acid esters.

(a)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2,3,5-trifluorobenzoicacid ethyl ester

A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a,4.03 g, 18.1 mmol), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester(4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L.,Priebe S. R., Sesnie J. A., Trehan A. K., J. Med. Chem., 1992;35(10):1764–1773), and triethylamine (18.0 mL, 129 mmol) in acetonitrile(50 mL) is heated at 50° C. under a nitrogen atmosphere for 4.5 hours.The yellow solution is concentrated in vacuo and poured into a saturatedNaHCO₃ solution. The mixture is then extracted with chloroform, and thecombined organic extracts are washed with brine, dried with Na₂SO₄,filtered, and concentrated in vacuo. The resulting residue is thenpurified by flash column chromatography (1:7 ethyl acetate/hexanes) toafford the title compound (5.24 g). ¹H NMR (CDCl₃): δ 7.35 (ddd, 1H),4.70–4.65 (bs, 1H), 4.42–4.20 (m, 3H), 3.90–3.62 (m, 3H), 3.58–3.42 (m,1H), 2.28–2.03 (m, 1H), 1.99–1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H).

(b)4-[(S)-3-tert-Butoxycarbonylaminopyrrolodin-1-yl]-2,3,6-trifluorobenzoicacid ethyl ester

A solution of 2,3,4,6-tetrafluorobenzoic acid ethyl ester (Example 1b,5.1 g, 22.9 mmol), triethylamine (22 mL, 157 mmol), and(S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (5.2 g, 27.9 mmol) inacetonitrile (60 mL) is stirred at room temperature for 64 hours. Themixture is concentrated in vacuo and the residue dissolved inchloroform, washed with NaHCO₃ and then brine, dried over Na₂SO₄,filtered, and concentrated under vacuum to afford a solid. The solid ispurified by column chromatography (1:1:7 ethylacetate/chloroform/hexanes) to afford the title compound (6.21 g). ¹HNMR (CDCl₃): δ 6.07 (ddd, 1H), 4.78–4.63 (bd, 1H), 4.49–4.22 (m, 3H),3.80–3.68 (m, 1H), 3.66–3.28 (m, 3H), 2.33–2.13 (m, 1H), 2.04–1.83 (m,1H), 1.45 (s, 9H), 1.36 (t, 3H).

(c)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoicacid ethyl ester

To a solution of 3-chloro-2,4,5-trifluorobenzoic acid ethyl ester(Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is addedtriethylamine (6.43 mL, 46.1 mmol) and (S)-pyrrolidin-3-ylcarbamic acidtert-butyl ester (4.72 g, 25.4 mmol). After 48 hours, the mixture isdiluted with ethyl acetate and washed with saturated NaHCO₃, water, andbrine. The organic layer is dried over MgSO₄, filtered, and the filtrateis concentrated to afford the title compound (9.34 g). MS CI: m/z 405(MH⁺).

(d)4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5,6-tetrafluorobenzoicacid benzyl ester

A solution of 2,3,4,5,6-pentafluorobenzoic acid benzyl ester (Example1d, 8.05 g, 26.6 mmol), triethylamine (26 mL, 186 mmol), and(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (5.6 g, 30 mmol) inacetonitrile (150 mL) is stirred at room temperature for 24 hours. Thesolvent is removed under vacuum and the residue dissolved in chloroform,washed with NaHCO₃ and then brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford a solid. The solid is then purified bycolumn chromatography (1:1:6 ethyl acetate/chloroform/hexanes) to yieldthe title compound as a solid (7.92 g). ¹H NMR (CDCl₃): δ 7.48–7.30 (m,5H), 5.35 (s, 2H), 4.77–4.50 (m, 1H), 4.37–4.19 (m, 1H), 4.01–3.63 (m,3H), 3.59–3.46 (m, 1H), 2.29–2.09 (m, 1H), 2.01–1.82 (m, 1H), 1.45 (s,9H).

(e) 4-(Pyrrolidin-1-yl)-2,5-difluorobenzoic acid ethyl ester

To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e,4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added triethylamine (5.9mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4 mmol). After 24 hours, thereaction mixture is diluted with ethyl acetate and washed with saturatedNaHCO₃, water, and brine. The organic layer is dried over MgSO₄,filtered, and the filtrate is concentrated to afford the title compoundas an oil (5.25 g). MS CI: m/z 256 (MH⁺).

(f)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluoro-3-methoxybenzoicacid ethyl ester

A solution of 2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester (Example1f, 2.821 g, 12.05 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester(3.310 g, 17.77 mmol), and triethylamine (9.13 g, 12.6 mL, 90.23 mmol)in acetonitrile (50 mL) is heated at 40° C. under nitrogen for 2 days.The yellow solution is concentrated to near dryness and poured intosaturated NaHCO₃ solution and extracted with dichloromethane. Thecombined organic extracts are washed with brine, dried over Na₂SO₄,filtered, and concentrated under vacuum. The resulting residue ispurified by flash column chromatography (1:7 ethyl acetate/hexanes) toafford the title compound as a yellow solid (3.743 g). MS EI: m/z 401(MH⁺).

(g)4-[3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoicacid ethyl ester

To a solution of 3-chloro-2,4,5-tri-fluorobenzoic acid ethyl ester(Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is addedtriethylamine (6.43 mL, 46.1 mmol) and pyrrolidin-3-ylcarbamic acidtert-butyl ester (4.72 g, 25.4 mmol). After 48 hours, the mixture isdiluted with ethyl acetate and washed with saturated NaHCO₃, water, andbrine. The organic layer is dried over MgSO₄, filtered, and the filtrateis concentrated to afford the title compound (9.2 g). MS CI: m/z 405(MH⁺).

4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic acidethyl ester

A solution of 2,3,4-trifluorobenzoic acid ethyl ester (Example 1g, 3.70g, 18.1 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g,21.6 mmol), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50mL) is heated at 50° C. under nitrogen atmosphere for 4.5 hours. Thesolution is concentrated in vacuo and poured into a saturated NaHCO₃solution. The mixture is then extracted with chloroform, and thecombined organic extracts are washed with brine, dried with Na₂SO₄,filtered, and the mixture concentrated in vacuo. The resulting residueis then purified by column chromatography (1:7 ethyl acetate/hexanes) toafford the title compound (4.70 g). ¹H NMR (CDCl₃): δ 7.59–7.49 (m, 1H),6.35–6.26 (m, 1H), 4.88–4.84 (bd, 1H), 4.39–4.28 (m, 3H), 3.81–3.50 (m,3H), 3.48–3.34 (m, 1H), 2.32–2.15 (m, 1H), 2.02–1.76 (m, 1H), 1.45 (s,9H), 1.40 (t, 3H).

(i) 4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluorobenzoicacid ethyl ester

To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e,14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07g, 86.2 mmol). After 45 hours, the reaction mixture is diluted withethyl acetate and washed with saturated NaHCO₃, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrate isconcentrated to afford an oil. The resulting residue is purified byflash chromatography (1:5 ethyl acetate/hexanes) to afford the titlecompound. MS (ES, M+1) m/z 371, mp 98–100° C.

The following compounds are synthesized according to general proceduresdescribed in Examples 2a–i above.

(k)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluoro-3-methylbenzoicacid ethyl ester (MS ES, MH⁺) m/z 385) using2,4,5-trifluoro-3-methylbenzoic acid ethyl ester (Example 1i) andpyrrolidin-3-ylcarbamic acid tert-butyl ester.

(l)4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoicacid ethyl ester (MS ES, MH⁺) m/z 399) using2,4,5-trifluoro-3-methylbenzoic acid ethyl ester (Example 1i) and3-(tert-butoxycarbonylaminomethyl)pyrrolidine (Rogers D. H., SaundersJ., Williams J. P., DE 19955794).

(m)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2,3-difluoro-5-methoxybenzoicacid ethyl ester (MS ES, MH⁺) m/z 401) using2,3,4-trifluoro-5-methoxybenzoic acid ethyl ester (Example 1h) andpyrrolidin-3-ylcarbamic acid tert-butyl ester.

(n)4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2,5-difluoro-3-methoxybenzoicacid ethyl ester (MS ES, MH⁺) m/z 415) using2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester (Example 1f) and3-(tert-butoxycarbonylaminomethyl)pyrrolidine (Rogers D. H., SaundersJ., Williams J. P., DE 19955794).

(o)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-3-ethoxy-2,5-difluorobenzoicacid ethyl ester. (¹H NMR (200 MHz, CDCl₃): δ 7.31 (dd, 1H), 4.71 (bs,1H), 4.34–3.4 (m, 9H), 2.23–1.81 (m, 2H), 1.45 (s, 9H), 1.37 (t, 3H),1.33 (t, 3H); ((MS ES, MH⁺) m/z 415.) using 3-ethoxy-2,5-difluorobenzoicacid ethyl ester (Sanchez J. P., Gogliotti R. D., Domagala J. M.,Gracheck S. J., Huband M. D., Sesnie J. A., Cohen M. A., Shapiro M. A.,J. Med. Chem., 1995; 38(22):4478–4487) and pyrrolidin-3-ylcarbamic acidtert-butyl ester.

(p)3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluorobenzoicacid ethyl ester (MS ES, MH⁺) m/z 504) using3-(benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid ethyl ester(Example 1j) and pyrrolidin-3-ylcarbamic acid tert-butyl ester.

(q)3-Chloro-2,5-difluoro-4-(3-[1,2,3]-triazol-1-ylpyrrolidin-1-yl)benzoicacid ethyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.79 (s, 1H), 7.65 (s, 1H),7.41–7.51 (m, 1H), 5.40–5.30 (m, 1H), 4.34–4.24 (q, 2H), 4.13–3.45 (m,4H), 2.65–2.50 (m, 1H), 2.43–2.28 (m, 1H), 1.34–1.27 (t, 3H)) using3-chloro-2,4,5-trifluorobenzoic acid ethyl ester (Example 1c) and1-pyrrolidin-3-yl-1H-[1,2,3]triazole (Singh R., Singh I. P., Thomas G.,Singh M. P., Micetich R. G., Fahti-Afshar R., Doerksen T. R., PCT Int.Appl., 1992, WO 9210492 A1).

EXAMPLE 3 Synthesis of 2-Substituted-Amino Benzoates

General Procedure

A solution of 4-(pyrrolidin-1-yl)-2-fluorobenzoic acid ethyl esters(Example 2) and cyclopropylamine (10–15 eq.) in dimethyl sulfoxide andtriethylamine (2–5 eq.) is heated in a sealed glass tube for 3 days at140° C. Compressed air is blown into the mixture to remove excesscyclopropylamine. The resulting solution is concentrated under vacuumand purified by column chromatography (ethyl acetate/hexanes) to afford4-(substituted pyrrolidin-1-yl)-2-cyclopropylamino-benzoic acid esters.

(a)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoicacid ethyl ester

A solution of4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5-trifluorobenzoicacid ethyl ester (Example 2a, 1.95 g, 5.01 mmol) and cyclopropylamine(14.0 mL, 201 mmol) in dimethyl sulfoxide (5 mL) is heated in a sealedglass tube for 44.5 hours at 100° C. Compressed air is blown into theblack solution to remove excess cyclopropylamine. The solution isconcentrated under high vacuum and purified by flash columnchromatography (1:9 ethyl acetate/hexanes) to afford the title compound(1.77 g). ¹H NMR (CDCl₃): δ 7.32 (dd, 1H), 4.81–4.67 (bs, 1H), 4.35–4.16(m, 3H), 3.95–3.40 (m, 4H), 2.92–2.80 (m, 1H), 2.25–2.08 (m, 1H),1.97–1.77 (m, 1H), 1.46 (s, 9H), 1.34 (t, 3H), 0.72–0.63 (m, 2H),0.57–0.49 (m, 2H).

(b)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,6-difluorobenzoicacid ethyl ester

A solution of4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,6-trifluorobenzoicacid ethyl ester (Example 2b, 5.4 g, 13.9 mmol), cyclopropylamine (40mL, 577 mmol), and dimethyl sulfoxide (28 mL) in a sealed glass tube isheated at 100° C. for 27 hours. The excess amine is removed by blowingin compressed air before the solution is concentrated under high vacuum.The residue is then purified by column chromatography (1:1:8 ethylacetate/chloroform/hexanes) to afford the title compound (4.80 g). ¹HNMR (CDCl₃): δ 7.42 (bs, 1H), 5.69 (ddd, 1H), 4.76–4.61 (m, 1H),4.37–4.19 (m, 3H), 3.81–3.66 (m, 1H), 3.65–3.43 (m, 2H), 3.39–3.28 (m,1H), 2.98–2.82 (m, 1H), 2.30–2.09 (m, 1H), 1.98–1.82 (m, 1H), 1.45 (s,9H), 1.34 (t, 3H), 0.72–0.68 (m, 2H), 0.67–0.44 (m, 2H).

(c)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoicacid ethyl ester

A solution of4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoicacid ethyl ester (Example 2c, 9.34 g, 23.1 mmol), cyclopropylamine (16mL, 228 mmol), and dimethyl sulfoxide (30 mL) is heated in a sealed tubeat 110° C. for 3 days. After cooling to room temperature, the reactionmixture is diluted with ethyl acetate and washed with saturated NaHCO₃,water, and brine. The organic layer is dried over MgSO₄, filtered, andthe filtrate is concentrated to afford a brown residue. The residue isthen purified via flash column chromatography (1:1 ethylacetate/hexanes) to afford the title compound (4.41 g). MS CI: m/z 442(MH⁺).

(d)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5,6-trifluorobenzoicacid benzyl ester

A solution of4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5,6-tetrafluorobenzoicacid benzyl ester (Example 2d, 2.5 g, 5.3 mmol), cyclopropylamine (40mL, 577 mmol), and dimethyl sulfoxide (20 mL) in a sealed glass tube isheated at 80° C. for 24 hours. The excess amine is removed by blowing incompressed air, and the solution is then concentrated under high vacuum.The residue is purified by column chromatography (1:1:7 ethylacetate/chloroform/hexanes) to afford the title compound as a solid(2.31 g). ¹H NMR (CDCl₃): δ 7.47–7.27 (m, 5H), 7.12 (bs, 1H), 5.30 (s,2H), 4.78–4.62 (m, 1H), 4.35–4.17 (m, 1H), 3.96–3.56 (m, 3H), 3.54–3.39(m, 1H), 2.91–2.73 (m, 1H), 2.24–2.02 (m, 1H), 1.96–1.77 (m, 1H), 1.45(s, 9H), 0.69–0.56 (m, 2H), 0.53–0.40 (m, 2H).

(e) 2-Cyclopropylamino-5-fluoro-4-pyrrolindin-1-ylbenzoic acid ethylester

4-(Pyrrolidin-1-yl)-2,5-difluorobenzoic acid ethyl ester (Example 2e,5.25 g, 20.6 mmol) and cyclopropylamine (30 mL, 428 mmol) are stirred indimethyl sulfoxide (30 mL) at 110° C. for 3 days in a sealed tube. Aftercooling to room temperature, the reaction mixture is diluted with ethylacetate and washed with saturated NaHCO₃, water, and brine. The organiclayer is dried over MgSO₄, filtered, and the filtrate concentrated toafford a brown residue. The residue is purified via flash columnchromatography (1:9 hexanes/dichloromethane) to afford the titlecompound as a solid (5.39 g). MS CI: m/z 293 (MH⁺).

(f)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminobenzoicacid ethyl ester

4-[3-(tert-Butoxycarbonylamino)-pyrrolidin-1-yl]-2,5-difluorobenzoicacid ethyl ester (Example 2j, 5.4 g, 13.9 mmol), isopropylamine (40 mL,469 mmol), and dimethyl sulfoxide (25 mL) are heated at 100° C. for 4days in a sealed glass tube. The excess amine is removed by blowing incompressed air. The residue is filtered and concentrated under vacuum toa thick oil. Purification by column chromatography (1:1:7 ethylacetate/chloroform/hexanes) to provide the title compound as a solid(1.6 g). MS: m/z 410 (MH⁺).

(g)4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-5-fluorobenzoicacid ethyl ester

4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoicacid ethyl ester (Example 2c, 1.95 g, 4.81 mmol), sec-butylamine (30 mL,296 mmol), and dimethyl sulfoxide (20 mL) are heated in a sealed glasstube at 110° C. for 24 hours. The reaction mixture is evaporated, andpurification by column chromatography (1:8, ethyl acetate/hexanes)provides the title compound as a yellow syrup (3.69 g). MS EI: m/z 458(MH⁺).

(h)4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid ethyl ester

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluoro-3-methoxybenzoicacid ethyl ester (Example 2f, 3.087 g, 7.71 mmol) and cyclopropylamine(12.0 mL, 172 mmol) in dimethyl sulfoxide (5 mL) is heated in a sealedglass tube for 3 days at 110° C. Compressed air is blown into the blacksolution to remove excess cyclopropylamine. The solution is concentratedunder vacuum and purified by flash column chromatography (1:5 ethylacetate/hexanes) to afford the title compound as a yellow solid (0.875g). ¹H NMR (CDCl₃): δ 7.33 (d, 1H), 7.15 (bs, 1H), 4.78–4.65 (m, 1H),4.33–4.15 (m, 3H), 3.92–3.50 (m, 3H), 3.55 (s, 3H), 3.45–3.34 (m, 1H),3.02–2.89 (m, 1H), 2.28–2.09 (m, 1H), 1.93–1.77 (m, 1H), 1.46 (s, 9H),1.34 (t, 3H), 0.7–0.59 (m, 2H), 0.49–0.42 (m, 2H).

(i)4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoicacid ethyl ester

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,5-difluorobenzoic acidethyl ester (2j, 3.059 g, 8.26 mmol) and cyclobutylamine (15.0 mL, 175mmol) in dimethyl sulfoxide (20 mL) is heated in a sealed vessel for 4days at 110° C. Compressed air is blown into the black solution toremove excess cyclobutylamine. The solution is concentrated under vacuumand purified by flash column chromatography (1:5 ethyl acetate/hexanes)to afford the title compound as a yellow solid (1.715 g). ¹H NMR(CDCl₃): δ 7.67 (bs, 1H), 7.48 (d, 1H), 5.54 (d, 1H), 4.77–4.64 (bs,1H), 4.38–4.18 (m, 3H), 3.97–3.85 (m, 1H), 3.80–3.42 (m, 3H), 3.41–3.30(m, 1H), 2.50–2.32 (m, 2H), 2.28–2.12 (m, 1H), 2.05–1.70 (m, 5H), 1.46(s, 9H), 1.35 (t, 3H).

(j)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoicacid ethyl ester

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic acidethyl ester (Example 2h, 1.85 g, 5.01 mmol) and cyclopropylamine (14.0mL, 201 mmol) in N,N-dimethylacetamide (5 mL) is heated in a sealedglass tube for 48 hours at 100° C. The solution is then concentratedunder high vacuum and purified by column chromatography (1:9 ethylacetate/hexanes) to afford the title compound (1.57 g). ¹H NMR (CDCl₃):δ 7.59 (bs, 1H), 7.57 (dd, 1H), 6.00 (dd, 1H), 4.82–4.68 (bd, 1H),4.39–4.18 (m, 3H), 3.80–3.49 (m, 3H), 3.41–3.30 (m, 1H), 3.00–2.88 (m,1H), 2.31–2.11 (m, 1H), 2.00–1.85 (m, 1H), 1.45 (s, 9H), 1.37 (t, 3H),0.73–0.50 (m, 4H).

(k)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoicacid ethyl ester

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2,3-difluorobenzoicacid ethyl ester (Example 21, 3.75 g, 9.3 mmol) and cyclopropylamine(14.0 mL, 201 mmol) in N,N-dimethylacetamide (5 mL) is heated in asealed glass tube for 48 hours at 100° C. The solution is thenconcentrated under high vacuum and purified by column chromatography(1:9 ethyl acetate/hexanes) to afford the title compound (2.0 g). ¹H NMR(CDCl₃): δ 7.64 (d, 1H), 7.56 (bs, 1H), 4.98–4.90 (bd, 1H), 4.40–4.20(m, 3H), 3.78–3.63 (m, 4H), 2.97–2.83 (m, 1H), 2.35–2.21 (m, 1H),1.93–1.81 (m, 1H), 1.46 (s, 9H), 1.38 (t, 3H), 0.75–0.61 (m, 2H),0.57–0.50 (m, 2H).

The following compounds are synthesized according to general proceduresExamples 3a–k described above.

(l)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid ethyl ester ([MS ES, MH⁺] m/z 422) using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluoro-3-methyl-benzoicacid ethyl ester (Example 2k).

(m)4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid ethyl ester. ([MS ES, M+1] m/z 436) using4-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoicacid ethyl ester (Example 2l).

(n)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-5-methoxybenzoicacid ethyl ester. ([MS ES, M+1] m/z 439) using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,3-difluoro-5-methoxybenzoicacid ethyl ester (Example 2m).

(o)4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid ethyl ester ([MS ES, MH⁺] m/z 453) using4-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-2,5-difluoro-3-methoxybenzoicacid ethyl ester (Example 2n)

(p)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-5-fluorobenzoicacid ethyl ester ([MS ES, MH⁺] m/z 452). using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-3-ethoxy-2,5-difluorobenzoicacid ethyl ester (Example 2o).

(q)3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoicacid ethyl ([MS ES, MH⁺] m/z 541) using3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2,5-difluorobenzoicacid ethyl ester (Example 2p).

(r)3-Chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3]-triazol-1-yl-pyrrolidin-1-yl)benzoicacid ethyl ester (¹H NMR (200 MHz, CDCl₃): δ 8.00 (s, 1H), 7.73 (s, 1H),7.52 (d, 1H), 7.19 (bs, 1H), 5.53–5.39 (m, 1H), 4.36–4.21 (q, 2H),4.14–4.01 (m, 1H), 3.98–3.83 (m, 1H), 2.71–2.58 (m, H), 2.43–2.29 (m,H), 1.41–1.28 (t, 3H), 0.73–0.59 (m, 2H), 0.52–0.37 (m, 2H)) using3-chloro-2,5-difluoro-4-(3-[1,2,3]-triazol-1-yl-pyrrolidin-1-yl)benzoicacid ethyl ester (Example 2q)

EXAMPLE 4 Ester Hydrolysis

General Procedure

A solution of 4-(substituted-pyrrolidin-1-yl)-2-cyclopropylaminobenzoicacid ester (Example 3) and aqueous sodium hydroxide (10–20 eq., 1.0N) intetrahydrofuran and methanol is heated for 16 to 24 hours at 70° C. Thesolution is cooled, diluted with water, and partially concentrated undervacuum. The resulting solution is acidified to pH 6 with aqueous 1.0Nhydrochloric acid, then the pH is adjusted to pH 7–8 with 5% NaHCO₃solution and extracted with ethyl acetate. The combined organic extractsare dried over Na₂SO₄, filtered, and concentrated in vacuo to afford4-(substituted-pyrrolidin-1-yl)-2-cyclopropylaminobenzoic acid.

(a)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoicacid

A solution of4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoicacid ethyl ester (Example 3a,1.40 g, 3.29 mmol) and aqueous sodiumhydroxide (1.33 N, 15.0 mL, 20.0 mmol) in tetrahydrofuran (20 mL) andmethanol (50 mL) is heated for 3 hours at 50° C. The solution is cooled,diluted with water, and partially concentrated in vacuo. The resultingsolution is acidified to pH 6 with aqueous 1N hydrochloric acid, andthen the pH is adjusted to pH 7–8 with 5% NaHCO₃ and extracted withchloroform. The combined organic extracts are dried over Na₂SO₄,filtered, and concentrated to give the title compound as a pale yellowsolid (1.31 g). ¹H NMR (DMSO-d₆): δ 12.65 (bs, 1H), 7.48 (bs, 1H),7.27–7.14 (m, 2H), 4.08–3.92 (m, 1H), 3.85–3.45 (m, 3H), 3.45–3.29 (m,1H), 2.86–2.74 (m, 1H), 2.10–1.91 (m, 1H), 1.89–1.72 (m, 1H), 1.39 (s,9H), 0.71–0.60 (m, 2H), 0.47–0.38 (m, 2H).

(b)4-[(S)-3-tert-Butoxycarbonylaminopyrridin-1-yl]-2-cyclopropylamino-3,6-difluorobenzoicacid

A solution of4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,6-difluorobenzoicacid ethyl ester (Example 3b, 1.45 g, 3.40 mmol) and aqueous sodiumhydroxide (1.33N, 17.0 mL, 22.6 mmol) in tetrahydrofuran (20 mL) andmethanol (50 mL) is heated for 21 hours at 50° C. The solution iscooled, diluted with water, and then partially concentrated in vacuo.The resulting solution is acidified to pH 6 with aqueous 1N hydrochloricacid, and then the pH is adjusted to pH 7–8 with 5% NaHCO₃ and extractedwith ethyl acetate three times. The combined organic extracts are driedover Na₂SO₄, filtered, and concentrated under vacuum to give the titlecompound as a pale green solid (1.33 g). ¹H NMR (DMSO-d₆): δ 7.21 (bd,1H), 5.83 (dd, 1H), 4.12–3.98 (m, 1H), 3.75–3.20 (m, 5H), 2.88–2.78 (m,1H), 2.14–1.96 (m, 1H), 1.90–1.73 (m, 1H), 1.39 (s, 9H), 0.69–0.59 (m,2H), 0.45–0.36 (m, 2H).

(c)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluoro-benzoicacid

To a solution of4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoicacid ethyl ester (Example 3c, 2.90 g, 6.56 mmol) in methanol (30 mL) andtetrahydrofuran (30 mL) is added a 1N solution of sodium hydroxide (50mL). The reaction mixture is stirred at 80° C. for 20 hours, cooled toroom temperature, and diluted with ethyl acetate. The organic layer iswashed with 1N hydrochloric acid, water, and brine. The organic layer isdried over MgSO₄, filtered, and filtrate concentrated to the titlecompound as a solid (2.74 g). MS CI: m/z 414 (MH⁺).

(d)4-[(S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5,6-trifluorobenzoicacid

A solution of benzyl4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5,6-trifluorobenzoate(Example 3d, 3.68 g, 7.31 mmol), 1.0 M NaOH (75 mL), methanol (50 mL),and tetrahydrofuran (50 mL) is heated at 50° C. for 24 hours. Themixture is partially concentrated under vacuum and then extracted withdichloromethane. The aqueous phase is brought to pH 7.5 using 1.0 M HCland extracted with ethyl acetate. The combined ethyl acetate extractsare dried over Na₂SO₄, filtered, and concentrated under vacuum to afford4-[(S)-3-tert-butoxycarbonylamino-pyrridin-1-yl]-2-cyclopropylamino-3,5,6-trifluoro-benzoicacid as a solid (2.9 g). This material is used without furtherpurification. ¹H NMR (DMSO-d₆): δ 7.19 (bd, 1H), 4.12–3.95 (m, 1H),3.83–3.52 (m, 3H), 3.48–3.33 (m, 1H), 2.83–2.69 (m, 1H), 2.10–1.94 (m,1H), 1.89–1.72 (m, 1H), 1.49 (s, 9H), 0.70–0.56 (m, 2H), 0.44–0.33 (m,2H).

(e) 2-Cyclopropylamino-5-fluoro-4-pyrrolidin-1-ylbenzoic acid

To a solution of 4-(pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoicacid ethyl ester (Example 3e, 3.10 g, 10.4 mmol) in methanol (50 mL) andtetrahydrofuran (20 mL) is added 1N solution of sodium hydroxide (35mL). The reaction mixture is stirred at 80° C. for 20 hours, cooled toroom temperature, and diluted with ethyl acetate. The organic layer iswashed with 1N hydrochloric acid, water, and brine. The organic layer isdried over MgSO₄, filtered, and the filtrate concentrated to afford thetitle compound as a solid (2.47 g). MS CI: m/z 263 (M⁺).

4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminobenzoicacid

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminobenzoicacid ethyl ester (Example 3f, 1.5 g, 3.40 mmol), aqueous 1 M sodiumhydroxide (50 mL), tetrahydrofuran (40 mL), and methanol (40 mL) areheated for 25 hours at 70° C. The solution is cooled, diluted withwater, and then partially concentrated. The resulting solution isacidified to pH 7–8 with aqueous 1.0 M hydrochloric acid and extractedwith ethyl acetate. The combined organic extracts are dried over Na₂SO₄,filtered, and concentrated under vacuum to give the title compound as asolid (1.25 g). MS EI: m/z 380 (M⁺).

(g)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-5-fluorobenzoicacid

A solution of4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-5-fluorobenzoicacid ethyl ester (Example 3g, 3.57 g, 7.79 mmol), 1.0N sodium hydroxide(50 mL), and methanol (80 mL) are heated at 80° C. for 16.5 hours. Themixture is partially evaporated, diluted with water (150 mL), and the pHadjusted to 7.0–8.0 using 1.0 M hydrochloric acid. The mixture isextracted with ethyl acetate, dried over Na₂SO₄, and concentrated undervacuum to give the title compound as an off-white solid (3.26 g) whichis used without further purification. MS EI: m/z 430 (M⁺).

(h)4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid

A solution of4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid ethyl ester (Example 3h, 0.173 g, 0.395 mmol) and aqueous sodiumhydroxide (1.33N, 2.0 mL, 2.66 mmol) in tetrahydrofuran (10 mL) andmethanol (30 mL) is heated for 22 hours at 70° C. The solution iscooled, diluted with water, and partially concentrated under vacuum. Theresulting solution is acidified to pH 6 with aqueous 1N hydrochloricacid, and then the pH is adjusted to pH 7–8 with 5% NaHCO₃ solution andextracted with ethyl acetate. The combined organic extracts are driedover Na₂SO₄, filtered, and concentrated in vacuo to afford the titlecompound as a yellow solid (0.160 g). ¹H NMR (CDCl₃): δ 7.46 (d, 1H),4.80–4.69 (bs, 1H), 4.33–4.18 (m, 1H), 3.90–3.45 (m, 3H), 3.62 (s, 3H),3.43–3.32 (m, 1H), 2.91–2.80 (m, 1H), 2.28–2.10 (m, 1H), 1.96–1.78 (m,1H), 1.46 (s, 9H), 0.63–0.52 (m, 4H).

(i)4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoicacid

A solution of4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoicacid ethyl ester (Example 3i, 1.51 g, 3.58 mmol) and aqueous sodiumhydroxide (1.33N, 20.0 mL, 26.6 mmol) in tetrahydrofuran (15 mL) andmethanol (40 mL) is refluxed for 19 hours. The solution is cooled,diluted with water, and partially concentrated under vacuum. Theresulting solution is acidified to pH 6 with aqueous 1.0N hydrochloricacid, and then the pH is adjusted to pH 7–8 with 5% NaHCO₃ solution andextracted with ethyl acetate. The combined organic extracts are driedover Na₂SO₄, filtered, and concentrated under vacuum to afford the titlecompound as a yellow solid (1.353 g). MS EI: m/z 394 (MH⁺).

(j)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoicacid

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoicacid ethyl ester (Example 3j, 1.34 g, 3.29 mmol) and aqueous sodiumhydroxide (2N, 20 mL) in tetrahydrofuran (20 mL) and methanol (20 mL) isrefluxed for 1 hour. The solution is partially concentrated in vacuo,then acidified to pH 6 and extracted with chloroform. The combinedorganic extracts are dried over Na₂SO₄, filtered, and concentrated togive the title compound (1.40 g). ¹H NMR (CDCl₃): δ 7.59 (dd, 1H), 6.06(dd, 1H), 4.80–4.70 (bd, 1H), 4.38–4.22 (m, 1H), 3.79–3.50 (m, 3H),3.47–3.35 (m, 1H), 2.98–2.87 (m, 1H), 2.30–2.14 (m, 1H), 1.97–1.84 (m,1H), 1.46 (s, 9H), 0.69–0.54 (m, 4H).

(k)4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoicacid

A solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoicacid ethyl ester (Example 3k, 2.00 g, 4.50 mmol) and aqueous sodiumhydroxide (2.0N, 20 mL) in tetrahydrofuran (20 mL), and methanol (20 mL)is refluxed for 1 hour. The solution is partially concentrated in vacuo,acidified to pH 6, and extracted with chloroform. The combined organicextracts are dried over Na₂SO₄, filtered, and concentrated to give thetitle compound (1.70 g). ¹H NMR (CDCl₃): δ 7.71 (d, 1H), 4.91–4.82 (bd,1H), 4.40–4.25 (m, 1H), 3.77–3.69 (m, 2H), 3.53–3.34 (m, 2H), 3.00–2.88(m, 1H), 2.24–2.15 (m, 1H), 1.90–1.80 (m, 1H), 1.46 (s, 9H), 0.72–0.54(m, 4H).

The following compounds are synthesized according to general proceduresof Examples 4a–k.

(l)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid ([MS ES, MH⁺] m/z 394.) using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid ethyl ester (Example 3l).

(m)4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid ([MS ES, M+1] m/z 408) using4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid ethyl ester (Example 3m).

(n)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-5-methoxybenzoicacid (¹H NMR (200 MHz, CDCl₃): δ 12.50 (bs, 1H), 7.18–7.09 (m, 1H), 7.07(d, 1H), 4.07–3.90 (m, 1H), 3.80–3.50 (m, 2H), 3.66 (s, 3H), 3.42–3.29(m, 2H), 2.88–2.71 (m, 1H), 2.10–1.91 (m, 1H), 1.86–1.67 (m, 1H), 1.39(s, 9H), 0.70–0.57 (m, 2H), 0.46–0.32 (m, 2H)) using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-5-methoxy-benzoicacid ethyl ester (Example 3n).

(o)4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid. ([MS ES, M+1] m/z 424) using4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid ethyl ester (Example 3o)

(p)4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-5-fluorobenzoicacid ([MS ES, MH⁺] m/z 424) using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-5-fluorobenzoicacid ethyl ester (Example 3p).

(q)3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoicacid (MS ES: m/z 513 (MH⁺]) using3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoicacid ethyl ester (Example 3q)

(r)3-Chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)benzoicacid (¹H NMR (200 MHz, CDCl₃): δ 8.50 (bs, 1H), 8.03 (s, 1H), 7.72 (s,1H), 7.60 (d, 1H), 7, 5.54–5.39 (m, 1H), 4.13–3.97 (m, 1H), 3.92–3.85(m, 1H), 3.68–3.63 (m, 1H), 3.54–3.42 (m, 1H), 3.10–3.00 (m, 1H),2.78–2.60 (m, 1H), 2.39–2.33 (m, 1H), 0.70–0.58 (m, 2H), 0.58–0.46 (m,2H)) using3-chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)benzoicacid ethyl ester (Example 3r).

EXAMPLE 5 Synthesis of N-Substituted Anthranilic Acids2-Cyclopropylamino-4,5-difluorobenzoic acid

To a solution of 4,5-difluoroanthranilic acid (1.13 g, 6.53 mmol) inanhydrous methanol (40 mL) is added molecular sieves (3 Å), acetic acid(3.70 mL, 65.3 mmol) and [(1-ethoxycyclopropyl)oxy]trimethylsilane (5.25mL, 26.11 mmol). After 30 minutes, sodium cyanoborohydride (2.08 g,32.64 mmol) is added, and the reaction mixture is heated to reflux.After 16 hours, the reaction is cooled to room temperature, filtered,washed with methanol, and the combined filtrate concentrated undervacuum to afford a viscous oil. The resulting oil is dissolved in ethylacetate and washed with 1.0 M hydrochloric acid, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrate isconcentrated under vacuum to afford as a beige solid (1.32 g). MS CI:m/z 212 (M⁺).

(b) 5-Chloro-2-cyclopropylamino-4-fluorobenzoic acid

To a solution of 4,5-difluoroanthranilic acid (1.20 g, 6.37 mmol) inanhydrous methanol (50 mL) is added molecular sieves (3 Å), acetic acid(3.70 mL, 65.3 mmol), and [(1-ethoxycyclopropyl)oxy]trimethylsilane(5.12 mL, 25.5 mmol). After 30 minutes, sodium cyanoborohydride (2.03 g,31.9 mmol) is added, and the reaction mixture is heated to reflux. After16 hours, the reaction is cooled to room temperature, filtered, washedwith methanol, and the combined filtrate concentrated under vacuum toafford a viscous oil. The resulting oil is dissolved in ethyl acetateand washed with 1.0 M hydrochloric acid, water, and brine. The organiclayer is dried over MgSO₄, filtered, and the filtrate is concentratedunder vacuum to afford as a beige solid (1.78 g). MS CI: m/e 228 (M⁺).

(c) 2-(2,4-Difluoroanilino)-4,5-difluorobenzoic acid

Lithium diisopropylamide is generated at −5° C. by combiningdiisopropylamine (7.2 mL, 51 mmol) and n-butyllithium (33 mL, 53 mmol)in anhydrous tetrahydrofuran (150 mL) under an inert atmosphere. After0.5 hour, the solution is cooled to −78° C. and 2,4-difluoroaniline(3.46 mL, 34 mmol) is added and stirred for 2 hours.2,4,5-Trifluorobenzoic acid (3.0 g, 17 mmol) is added, and the mixtureis subsequently allowed to warm to room temperature over 18 hours. Asaturated solution of hydrogen chloride/dioxane (10 MIL) is added, andafter 1 hour, the mixture is concentrated to a solid. The solid isdissolved in chloroform and washed with 1.0 M hydrochloric acid, water,and brine. The solution is dried, concentrated in vacuo, and purified bycolumn chromatography (3:1 ethyl acetate/hexanes) to give2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid as a solid (2.18 g). ¹HNMR (CDCl₃): δ 8.95 (bs, 1H), 7.80–7.75 (m, 2H), 7.50–6.85 (m, 3H),6.62–6.40 (m, 1H). MS EI: m/z 286 (M⁺).

(d) 3-Chloro-2-cyclopropylamino-4,5-difluorobenzoic acid

In a sealed tube a mixture of 2-bromo-3-chloro-4,5-difluorobenzoic acid(Example 20, 7.96 g, 29.3 mmol), cyclopropyl amine (4.20 mL, 58.7 mmol),potassium acetate (5.77 g, 58.6 mmol), cupric acetate monohydrate (0.50g, 2.5 mmol), and triethylamine (4.9 mL, 35.19 mmol) in isopropylalcohol is stirred at 80° C. After 16 hours, the reaction mixture isconcentrated under vacuum, and the resulting residue is dissolved inethyl acetate. The organic layer is washed with 1.0 M hydrochloric acid,water, and brine. The organic layer is dried over MgSO₄ and filtered.The filtrate is concentrated under vacuum and purified via flash columnchromatography (5% isopropyl alcohol/1% formic acid/94% dichloromethane)to afford the title compound (4.62 g). MS CI: m/z 248 (MH⁺).

EXAMPLE 6 Synthesis of Hydrazinecarboxylic t-Butyl Esters(2-Cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylic acidtert-butyl ester

To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5)(1.32 g, 6.19 mmol) and tert-butyl carbazate (1.30 g, 9.75 mmol) indichloromethane (30 mL) is added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.87 g, 9.75 mmol).After 16 hours, the reaction mixture is diluted with dichloromethane andwashed with saturated NaHCO₃, water, and brine. The organic layer isdried over MgSO₄ and filtered. The filtrate is concentrated under vacuumand purified via flash column chromatography (1:2 ethyl acetate/hexanes)to afford N₂-(2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylicacid tert-butyl ester as a solid (1.65 g). MS EI: m/z 328 (M⁺).

(b) [2-(2,4-Difluoroanilino)-4,5-difluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester

To a solution of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid(Example 5, 2.18 g, 7.6 mmol) and tert-butyl carbazate (1.57 g, 11.8mmol) in dichloromethane (30 mL) is added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.25 g, 11.77 mmol).After stirring for 16 hours at room temperature, the reaction mixture isdiluted with dichloromethane and then washed with saturated NaHCO₃,water, and brine. The organic layer is dried over Na₂SO₄, concentratedunder vacuum, and purified via column chromatography (1:3 ethylacetate/hexanes) to afford[2-(2,4-difluoroanilino)-4,5-difluorobenzoyl]-hydrazinecarboxylic acidtert-butyl ester as a solid (2.20 g). MS EI: m/z 400 (M⁺).

(c)(3-Chloro-2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylicacid tert-butyl ester

To a solution of 3-chloro-2-cyclopropylamino-4,5-difluorobenzoic acid(Example 5d, 2.09 g, 8.45 mmol) in dichloromethane (30 mL) is addedtert-butyl carbazate (1.67 g, 12.7 mmol) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.43 g, 12.7 mmol).After 16 hours, the reaction mixture is diluted with dichloromethane andwashed with saturated NaHCO₃, water, and brine. The organic layer isdried over MgSO₄ and filtered. The filtrate is concentrated under vacuumand purified via flash column chromatography (1:2 ethyl acetate/hexanes)to afford the title compound (1.93 g). MS EI: m/z 360 (M⁺).

(d) (5-Chloro-2-cyclopropylamino-4-fluorobenzoyl)-hydrazinecarboxylicacid tert-butyl ester

To a solution of 5-chloro-2-cyclopropylamino-4-fluorobenzoic acid(Example 5, 1.48 g, 6.46 mmol) in dichloromethane (50 mL) is addedtert-butyl carbazate (1.28 g, 9.69 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbo-diimide (1.86 g, 9.69 mmol).After 16 hours, the reaction mixture is diluted with dichloromethane andwashed with saturated NaHCO₃, water, and brine. The organic layer isdried over MgSO₄ and filtered. The filtrate is concentrated under vacuumand purified via flash column chromatography (1:2 ethyl acetate/hexanes)to afford(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylicacid tert-butyl ester as a solid (1.04 g). MS CI: m/e 344 (M⁺+1).

EXAMPLE 7 Synthesis of 4-Heterocyclic-benzoylhydrazinecarboxylic acidt-butyl esters

General Procedure A

A solution of a substituted benzoylhydrazinecarboxylic acid tert-butylester from Example 6 (where R₇=F), heterocyclic amine (2 eq.), andtriethylamine (10 eq.) is stirred in dimethyl sulfoxide orN,N-dimethylformamide (6 mL) at 120° C. in a sealed tube for 16 hours.After cooling to room temperature, the reaction mixture is diluted withethyl acetate and washed with saturated NaHCO₃, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrateconcentrated to afford a brown residue. Trituration with diethyl etheror purification via flash column chromatography (ethyl acetate/hexanes)yields the product.

General Procedure B

To a suspension of a benzoic acid of Example 4 (3.30 mmol) andtert-butyl carbazate (1.5 eq.) in anhydrous dichloromethane is added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.5 eq.).The mixture is stirred at room temperature for 20 hours, poured intosaturated NaHCO₃, and extracted with dichloromethane. The combinedorganic extracts are washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification by flash column chromatography(ethyl acetate/hexanes) afford the title compounds.

The following compounds are synthesized according to General ProceduresA or B above:

(a)N′-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 508 (MH⁺)) using(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) and3-(tert-butoxycarbonylaminomethyl)pyrrolidine (General Method A).

(b)N′-4-[4-(tert-Butoxycarbonylpiperazin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 494 (MH⁺)) using(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) and 4-tert-butoxycarbonylpiperazine(General Method A).

(c)N′-{4-[3-(tert-Butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 522 (MH⁺)) using(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) and3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidine (Sanchez J. P.,Bridges A. J., Bucsh R., Domagala J. M., Gogliotti R. D., Hagen S. E.,Heifetz C. L., Joannides E. T., Sesnie J. C., et al. J. Med. Chem.,1992; 35(2):361–367) (General Method A).

(d)N′-[4-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 506 (MH⁺)) using(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) and (3-azabicyclo[3.1.0]hex-6-yl)carbamicacid tert-butyl ester (Brighty K. E., 1991, EP 413455] (General MethodA).

(e)N′-{4-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 508 (MH⁺)) using(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) and(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidine (Chu D. T., Li Q.,Cooper C. S., Fung A. K. L., Lee C. M., Plattner J. J., PCT Int. Appl.,1995:255. WO 9510519) (General Method A).

(f)N′-{4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-(2,4-difluoroanilino)-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 566 (MH⁺)) using[2-(2,4-difluoroanilino)-4,5-difluorobenzoyl]-hydrazinecarboxylic acidtert-butyl ester (Example 6b) and (S)-pyrrolidin-3-ylcarbamic acidtert-butyl ester (General Method A).

(g)N′-{4-[(S)-3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester MS CI: m/z 538 (MH⁺) using4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoic(Example 4a) (General Method B).

(h)N′-{4-[(S)-3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,6-difluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (¹H NMR (CDCl₃): δ 8.08 (bs, 2H), 6.50 (bs, 1H),5.70 (dd, 1H), 4.76–4.68 (m, 1H), 4.37–4.23 (m, 1H), 3.78–3.68 (m, 1H),3.65–3.42 (m, 2H), 3.40–3.30 (m, 1H), 2.96–2.83 (m, 1H), 2.28–2.14 (m,1H), 2.00–1.84 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 0.68–0.61 (m, 2H),0.58–0.48 (m, 2H)) using4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,6-difluorobenzoicacid (Example 4b) (General Method B).

(i)N′-{4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5,6-trifluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (¹H NMR (CDCl₃), δ 8.04 (bd, 1H), 7.55(bs, 1H), 6.52 (bs, 1H), 4.79–4.67 (m, 1H), 4.37–4.19 (m, 1H), 3.97–3.55(m, 3H), 3.53–3.40 (m, 1H), 2.90–2.75 (m, 1H), 2.29–2.06 (m, 1H),1.96–1.75 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 0.69–0.57 (m, 2H),0.54–0.43 (m, 2H)) using4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-2-cyclopropylamino-3,5,6-trifluorobenzoicacid (Example 4d) (General Method B).

(j)N′-{4-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylictert-butyl ester (MS CI: m/z 528 (MH⁺)) using4-[(S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoicacid (Example 4c) (General Method B).

(k)N′-[(S)-4-(7-tert-Butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 520 (MH⁺)) using(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) and (5-azaspiro[2,4]hept-7-yl)carbamicacid tert-butyl ester (General Method A).

(l)N′-{4-[(R)-3-(1-tert-Butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 570 (MH⁺)) using(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylicacid tert-butyl ester (Example 6c) and[(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidine (Fedij V.,Lenoir E. A., III, Suto M. J., Zeller J. R., Wemple J., Tetrahedron:Asymmetry, 1994; 5[7]:1131–1134) (General Method A).

(m)N′-[4-(Pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]-hydrazinecarboxylictert-butyl ester (MS CI: m/z 379 (MH⁺)) using2-cyclopropylamino-5-fluoro-4-pyrrolidin-1-ylbenzoic acid (Example 4e)(General Method B).

(n)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminobenzoyl}hydrazinecarboxylic acid tert-butyl ester (MS EI: m/z 496 (MH⁺)) using4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminobenzoicacid (Example 4f) (General Method B).

(o)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS EI: m/z 544 (MH⁺)) using4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-5-fluorobenzoicacid (Example 4g) (General Method B).

(p)N′-{4-[3-tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS EI: m/z 524 (MH⁺)) using4-[3-tert-butoxycarbonylamino)-pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid (Example 4h) (General Method B).

(q)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS EI: m/z 394 (M⁺)) using4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoicacid (Example 4i) (General Method B).

(r)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS EI: m/z 494 (MH⁺)) using4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoicacid (Example 4j) (General Method B).

(s)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (¹H NMR (CDCl₃): δ 8.77 (bs, 1H), 7.35 (d, 1H),6.82 (bs, 1H), 6.55 (bs, 1H), 5.01–4.97 (m, 1H), 4.29 (bs, 1H),3.74–3.57 (m, 2H), 3.41–3.24 (m, 2H), 2.84–2.75 (m, 1H), 2.33–2.16 (m,1H), 1.92–1.72 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H), 0.69–0.62 (m, 2H),0.60–0.50 (m, 2H)) using4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoicacid (Example 4k) (General Method B).

(t)N′-[4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-3-methylbenzoyl]hydrazinecarboxylicacid tert-butyl ester ([MS ES, MH+] m/z 508) using4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-3-methylbenzoicacid (Example 4l) (General Method B).

(u)N′-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methylbenzoyl)hydrazinecarboxylicacid tert-butyl ester ([MS ES, MH⁺] m/z 522) using4-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-31-methylbenzoicacid (Example 4m) (General Method B).

(v)N′-[4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-5-methoxybenzoyl]hydrazinecarboxylicacid tert-butyl ester. ([MS ES, MH⁺] m/z 525) using4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-5-methoxybenzoicacid (Example 4n) (General Method B).

(w)N′-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoyl}hydrazinecarboxylicacid tert-butyl ester ([MS ES, MH₂ ⁺²] m/z 539) using4-[3-(tert-butoxycarbonylamino-methyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoicacid (Example 4o) (General Method B).

(x)N′-[3-(Benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester. ([MS ES, MH⁺] m/z 627) using3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoicacid (Example 4q) (General Method B)

(y)N′-[3-Chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)benzoyl]hydrazinecarboxylicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 9.90 (bs, 1H), 7.97(s, 1H), 7.72 (s, 1H, 7.52 (d, 1H), 7.17 (bs, 1H), 5.51–5.41 (m, 1H),4.59 (bs, 1H), 4.06–3.95 (m, 1H), 3.87–3.74 (m, 1H), 3.61–3.55 (m, 1H),3.48–3.36 (m, 1H), 2.97–2.90 (m, 1H), 2.77–2.59 (m, 1H) 2.42–2.31 (m,1H), 1.46 (s, 9H), 0.68–0.50 (m, 4H)) using3-chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-ylpyrrolidin-1-yl)benzoicacid (Example 4r) (General Method B).

(z)N-(1-{4-[3-(tert-Butoxycarbonylaminomethyl)-piperidin-1-yl]-2-cyclopropylamino-5-fluorophenyl}methanoyl)hydrazinecarboxylicacid tert-butyl ester (MS CI: m/e 522 (MH+)) frompiperidin-3-ylmethylcarbamic acid tert-butyl ester (Hilpert K.,Ackermann J., Banner D. W., Gast A., Gubernator K., Hadvary P., LablerL., Mueller K., Schmid G., et al., J. Med. Chem., 1994;37[23]:3889–3901) and(2-Cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) (General Method A).

(aa)N-[1-(4-{3-[(tert-Butoxycarbonylisopropylamino)-methyl]-pyrrolidin-1-yl}-2-cyclopropylamino-5-fluorophenyl)methanoyl]-hydrazinecarboxylicacid tert-butyl ester (MS CI: m/e 550 (MH+)) usingisopropylpyrrolidin-3-ylmethylamine (Mich T. F., Culbertson T. P., U.S.Pat. No. 4,550,103) and(2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylic acidtert-butyl ester (Example 6a) (General Method B).

(bb)N′-(1-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-5-chloro-2-cyclopropylaminophenyl}methanoyl)hydrazinecarboxylicacid tert-butyl ester (MS CI: m/e 524 [M⁺+1]) using(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylicacid tert-butyl ester (Example 6c) and3-(tert-butoxycarbonylaminomethyl)pyrrolidine (General Method A).

(cc)N′-[4-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS ES: m/z 537 (MH⁺)) from(4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-5-fluorobenzoicacid (Example 4p) (General Method A).

EXAMPLE 8 Synthesis of(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acid tert-butylesters

General Method A

To a solution of a benzoylhydrazinecarboxylic acid tert-butyl ester(from Example 7 (0.435 mmol) in tetrahydrofuran (15 mL) is addedpotassium carbonate (0.300 g, 2.18 mmol) and triphosgene (0.167 g, 0.566mmol). The reaction mixture is refluxed for 90 minutes, cooled to roomtemperature, and diluted with ethyl acetate. The organic layer is washedwith water and brine, then dried over MgSO₄, and filtered. The filtrateis concentrated under vacuum and purified by flash column chromatography(ethyl acetate/hexanes) to afford the title compounds.

General Method B

A solution of (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acidtert-butyl ester (such as, for example, Example 14), pyrrolidine sidechain (2 eq.), and triethylamine (10 eq.) are stirred in dimethylsulfoxide or acetonitrile (3 mL) at 80° C. for 48 hours. After coolingto room temperature, the reaction mixture is diluted with ethyl acetateand washed with saturated NaHCO₃, water, and brine. The organic layer isdried over MgSO₄, filtered, and concentrated. The resulting residue ispurified via flash column chromatography (ethyl acetate/hexanes) toafford the title compounds General Method C

To a solution of a C-6- and/orC-8-halogenated-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acidtert-butyl ester in ethanol and tetrahydrofuran is added triethylamineand 20% palladium on carbon. Hydrogen is introduced to the reactionmixture at high pressure for several days, then the reaction mixture isfiltered through Celite, washed with ethanol, and the combined filtrateconcentrated in vacuo and purified via flash column chromatography(ethyl acetate/hexanes) to afford the title compounds.

General Method D

A suspension of benzoylhydrazinecarboxylic acid tert-butyl ester (fromExample 7) and triethylamine (10 eq.) are stirred in anhydroustetrahydrofuran for 5 minutes. Phosgene (20% solution in toluene, 2 eq.)is added in one portion to the suspension. The reaction mixture isheated at 60° C. for 4.5 hours, cooled to room temperature, poured intosaturated NaHCO₃ solution, and extracted with chloroform. The combinedorganic extracts are washed with water, brine, and then dried overNa₂SO₄, filtered, and concentrated under vacuum. The resulting residueis purified by flash column chromatography (1:1 ethyl acetate/hexanes)to afford the title compounds.

General Method E

An appropriately substituted pyrrolidine (1.5–2 eq.), a3-dibenzylamino-6, 7-difluoro-1-substituted-1H-quinazoline-2,4-dione(Example 16) (1 eq.), and triethylamine (10 eq.) are combined inacetonitrile and heated to reflux for 72 hours. The solution is cooled,concentrated, and re-dissolved in chloroform. The organic solution iswashed with 1.0 N hydrochloric acid, saturated NaHCO₃, brine, and driedover magnesium sulfate. The solution is concentrated to give the titlecompounds.

General Method F

A solution of (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acidtert-butyl ester (such as, for example, Example 14), pyrrolidine sidechain (2 eq.), and triethylamine (10 eq.) are stirred in dimethylsulfoxide or acetonitrile (3 mL) at 80° C. for 20 to 40 hours. Aftercooling to room temperature, the reaction mixture is diluted with ethylacetate and washed with saturated NaHCO₃, water, and brine. The organiclayer is dried over MgSO₄, filtered, and concentrated. The resultingresidue is redissolved in methylene chloride and then treated withdi-tert-butyl dicarbonate (2 eq). After 1 hour, the reaction mixture isconcentrated and the product purified via flash column chromatography(ethylacetate/hexanes) to afford the title compounds.

The following compounds are synthesized according to General ProceduresA–F of Example 8:

(a){7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 568 (MH+)) fromN′-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 18a) (General Method A)

(b)7-[4-(tert-Butoxycarbonylpiperazin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 554 (MH+)) fromN′-4-[4-(tert-butoxycarbonylpiperazin-1-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 18b) (General Method A).

(c){7-[3-(tert-Butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 582 (MH+)) fromN′-{4-[3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 18c) (General Method A).

(d)[7-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-carbamicacid tert-butyl ester (MS CI: m/z 566 (MH⁺)) fromN′-[4-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 18d) (General Method A).

(e){7-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (MS CI: m/z 568 (MH⁺)) fromN′-{4-[(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluoro-benzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 18e) (General Method A).

(f){7-[(S)-3-(tert-Butoxycarbonylamino)pyrolidin-1-yl]-8-chloro-1-(2,4-difluoroanilino)-6-fluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (¹H NMR (CDCl₃): δ 7.45–7.38 (m, 1H), 6.97–6.81(m, 1H), 6.73–6.66 (m, 1H), 6.54–6.42 (m, 1H), 4.90–4.81 (bs, 1H),4.31–4.21 (bs, 1H), 3.86–3.36 (m, 4H), 2.32–2.04 (m, 1H), 1.96–1.84 (m,1H), 1.61 (s, 9H), 1.45 (s, 9H)) fromN′-{4-[(S)-3-(tert-butoxycarbonyl-N-amino)-pyrrolidin-1-yl]-3-chloro-2-(2,4-difluoroanilino)-5-fluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 18f) (General Method A).

(g)7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl-1-cyclopropylamino-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (¹H NMR (CDCl₃): δ 7.54 (dd, 1H), 6.67 (bs, 1H),4.79–4.68 (bs, 1H), 4.39–4.23 (m, 1H), 4.10–3.65 (m, 3H), 3.58–3.45 (m,1H), 3.37–3.25 (m, 1H), 2.30–2.11 (m, 1H), 2.03–1.86 (m, 1H), 1.50 (s,9H), 1.47 (s, 9H), 1.20–1.12 (m, 2H), 0.83–0.74 (bs, 2H)) fromN′-{4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5-difluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 5g) (General Method A).

(h){7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (MS CI: m/z 538 (M⁺)) fromN′-{4-[(S)-3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,6-difluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 5h) (General Method A).

(i){7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl-3-carbamicacid tert-butyl ester (MS CI: m/z 556 (MH⁺)) fromN′-{4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3,5,6-trifluorobenzoyl}hydrazinecarboxylic acid tert-butyl ester (Example 5i) (General Method A)

(j){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 552 (MH⁺)) fromN′-{4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluoro-benzoyl}hydrazinecarboxylictert-butyl ester (Example 5j) (General Method A).

(k)[7-(3-Hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 467 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and 3-Hydroxymethylpyrrolidine(Roussi G., Zhang J., Tetrahedron Lett., 1988; 29(28):3481–3482)(General Method B).

(l){7-[3-(tert-Butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester (MS CI: m/z 580 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and3-(tert-butoxycarbonylaminoethyl)pyrrolidine (Antonsson K. T., Bylund R.E., Gustafsson N. D., Nilsson N. O. I. WO 9429336) (General Method B).

(m)[7-(7-tert-Butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-carbamicacid tert-butyl ester (MS CI: m/z 580 (MH⁺)) fromN′-[(S)-4-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 18g) (General Method A).

(n){7-[(R)-3-(1-tert-Butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 596 (MH⁺) fromN′-{4-[(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7l) (General Method A).

(o){7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 534 (MH⁺)) from{7-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8a) (General Method C).

(p)[7-(Pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 437 (MH⁺)) usingN′-[4-(Pyrrolidin-1-yl)-3-chloro-2-cyclopropylamino-5-fluoro-benzoyl]hydrazinecarboxylictert-butyl ester (Example 18h) (General Method A).

(q){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-6-fluoro-1-isopropyl-2,4-dioxo-6-fluoro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester. (MS EI: m/z 530 (M⁺)) usingN′-{4-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl)-3-chloro-5-fluoro-2-isopropylaminobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 18i) (General Method A).

(r){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-sec-butyl-8-chloro-6-fluoro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS EI: m/z 570 (MH⁺)) usingN′-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-sec-butylamino-3-chloro-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7o) (General Method A).

(s){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS EI: m/z 550 (MH⁺)) usingN′-{4-[3-tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7p) (General Method D).

(t){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS EI: m/z 568 (MH⁺)) usingN′-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 7q) (General Method A).

(u){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-8-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS EI: m/z 520 (MH⁺)) usingN′-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7r) (General Method D).

(v){7-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-6-chloro-1-cyclopropyl-8-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (¹H NMR (CDCl₃): δ 7.36 (d, 1H), 6.64 (bs, 1H),4.86–4.80 (bd, 1H), 4.31–4.25 (m, 1H), 3.81–3.66 (m, 2H), 3.51–3.31 (m,2H), 3.02–2.97 (m, 1H), 2.32–2.22 (m, 1H), 1.95–1.85 (m, 1H), 1.63 (s,9H), 1.46 (s, 9H), 0.77–0.73 (m, 2H), 0.63–0.57 (bs, 2H)) usingN′-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7s) (General Method D).

(w)[(S)-1-(1-Cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (MS CI, m/z 614 (MH⁺)) using3-dibenzylamino-6,7-difluoro-1-cyclopropylmethyl-1H-quinazoline-2,4-dione(Example 17a) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester(General Method E).

(x){1-[(R)-1-(Cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl}-carbamicacid tert-butyl ester (MS CI: m/z 656 (MH⁺)) using3-dibenzylamino-6,7-difluoro-1-cyclopropylmethyl-1H-quinazoline-2,4-dione(Example 17a) and(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidine (GeneralMethod E).

(y)[(S)-1-(3-Dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (mp 104–106° C., MS CI: m/z 588 (MH⁺)) using3-dibenzylamino-6,7-difluoro-1-ethyl-1H-quinazoline-2,4-dione (Example17b) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (GeneralMethod E).

(z)[(R)-1-(3-Dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-1-methyl-1-pyrrolidin-3-ylethyl]carbamicacid tert-butyl ester (MS CI: m/z 630 (MH⁺)) using3-dibenzylamino-6,7-difluoro-1-ethyl-1H-quinazoline-2,4-dione (Example17b) and (R)-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidine(General Method E).

(aa)[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester ([MS ES, MH⁺] m/z 534) usingN′-[4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-3-methylbenzoyl]-hydrazinecarboxylicacid tert-butyl ester (Example 7t) (General Method D).

(bb){7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (MS ES, MH⁺) m/z 548)) usingN′-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methylbenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7u) (General Method D.

(cc)[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester ([MS ES, MH₂ ⁺] m/z 551) usingN′-[4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-3-fluoro-5-methoxybenzoyl]-hydrazinecarboxylicacid tert-butyl ester (Example 7v) (General Method D).

(dd){7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester ([MS ES, MH₂ ⁺²] m/z 565) usingN′-{4-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluoro-3-methoxybenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7w) (General Method D).

(ee)[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester ([MS ES, MH₂ ⁺²] m/z 565) fromN′-[4-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-2-cyclopropylamino-3-ethoxy-5-fluorobenzoyl]-hydrazinecarboxylicacid tert-butyl ester (Example 7 cc) (General Method A).

(ff)[7-(3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-8-cyano-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester ([MS ES, MH⁺] m/z 545) fromN′-[3-(benzyloxyiminomethyl)-4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-cyclopropylamino-5-fluoro-benzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 7x) (General Method A).

(gg)[8-Chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.96 (s, 1H), 7.74 (s,1H), 7.29 (d, H), 6.26 (bs, 1H), 5.51–5.39 (m, 1H), 4.17–4.07 (m, 1H),3.99–3.88 (m, 1H), 3.71–3.66 (m, 1H), 3.57–3.45 (m, 1H), 3.15–3.05 (m,1H), 2.74–2.60 (m, 1H), 2.44–2.32 (m, 1H), 1.64 (s, 9H), 0.76–0.49 (m,4H)) fromN′-[3-chloro-2-cyclopropylamino-5-fluoro-4-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)benzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 7y) (General Method A).

(hh)[7-(3-Carbamoylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 496 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and 3-carbamoyl-piperidine (GeneralMethod B).

(ii){7-[(trans-3-(tert-Butoxycarbonylaminomethyl)-4-trifluoromethyl-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 635 (M⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-carbamicacid tert-butyl ester (Example 14) andtrans-3-(tert-butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidine(Li Q., Wang W., Berst K. B., Claiborne A., Hasvold L., Raye K., TufanoM., et al., J. Med. Chem. Lett., 1998; 8[15]:1953–1958) (General MethodB).

(jj)8-Chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-{3-[(2,2,2-trifluoro-ethylamino)methyl]pyrrolidin-1-yl}-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (MS CI: m/z 548 (M⁺)) using(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and{3-[(2,2,2-trifluoroethylamino)methyl]pyrrolidin-1-yl}carbamic acidtert-butyl ester (Domagala J. M., Mich T. F., Sanchez J. P. U.S. Pat.No. 5,097,032) (General Method B).

(kk)[8-Chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 494 (MH⁺)) using(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and5-methyloctahydropyrrolo[3,4-c]pyrrole (Ohnmacht C. J. Jr., Draper C.W., Dedinas R. F., Loftus P., Wong J. J., J. Heterocycl. Chem., 1983;20[2]:321–329) (General Method B).

(ll)[8-Chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 494 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and(2,7-diaza-spiro[4.4]non-2-yl)carbamic acid tert-butyl ester (CulbertsonT. P., Sanchez J. P., Gambino L., Sesnie J. A., J. Med. Chem., 1990;33(8):2270–2275) (General Method B).

(mm)(7-[3-Benzyl-3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (MS CI: m/z 658 (MH⁺)) using(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and(3-benzylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester (ExampleA7o) (General Method B).

(nn){7-[(R)-3-((S)-1-tert-Butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester ((MS CI: m/z 582 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and(R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (JohnsonD. R., Szoteck D. L., Domagala J. M., Stickney T. M., Michel A., KampfJ. W., J. Heterocycl. Chem., 1992; 29[6]:1481–1488) (General Method B).

(oo)[8-Chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyiminopyrrolidin-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 469 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and pyrrolidin-3-one oxime (ExampleA7) (General Method B).

(pp)[7-trans-(3-tert-Butoxycarbonylamino-4-trifluoromethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-carbamicacid tert-butyl ester (MS CI: m/z 622 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) andtrans-(4-trifluoromethylpyrrolidin-3-yl)carbamic acid tert-butyl ester(Fukui H., Shibata T., Naito T. Nakano J., Maejima T., Senda H., IwataniW., et al., Bioorg. Med. Chem. Lett., 1998; 8[20]:2833–2838) (GeneralMethod B).

(qq) (7-{(R)-3-(S)-1-(tert-Butoxycarbonylmethylamino) ethyl]pyrrolidin-1-yl}-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (MS CI: m/z 596 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and(R)-3-((S)-1-methylaminoethyl)pyrrolidine (J. Het. Chem., 1992; 29:1481)(General Method F).

(rr)trans-[7-((3-tert-Butoxycarbonylamino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (MS CI: m/z 630 (MH⁺)) using(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) andtrans-4-phenylpyrrolidin-3-ylamine carbamic acid tert-butyl ester (BucshR. A., Domagala J. M., Laborde E., Sesnie J. C., J. Med. Chem., 1993;36[26]:4139–1451) (General Method B).

(ss)trans-{7-[3-tert-Butoxycarbonylamino-4-(4-hydroxyphenyl)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (MS: m/z 646 (MH⁺)) using(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) andtrans-4-(4-hydroxyphenyl)-pyrrolidin-3-ylamine carbamic acid tert-butylester (Bucsh R. A., Domagala J. M., Laborde E., Sesnie J.C., J. Med.Chem., 1993; 36[26]:4139–4151) (General Procedure B).

(tt){7-[3-(tert-Butoxycarbonylaminomethyl)piperidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 580 (M⁺)) using(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and (piperidin-3-ylmethyl)carbamicacid tert-butyl ester (General Method B).

(uu)(7-{3-[(tert-Butoxycarbonylisopropylamino)methyl]pyrrolidin-1-yl}-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-carbamicacid tert-butyl ester (MS CI: m/z 608 (M⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and3-(isopropylaminomethyl)pyrrolidine (Domagala et al., J. Med. Chem.,1994; 3889–3901) (General Method F).

(vv){7-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-6,8-dichloro-1-cyclopropyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS CI: m/z 584 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and (pyrrolidine-3-ylmethyl)carbamicacid tert-butyl ester (General Method B).

(ww)[7-(3-tert-Butoxycarbonylamino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃) δ 7.68 (d, 1H), 7.50–7.29(m, 5H), 6.72 (s, 1H), 5.24 (s, 1H), 4.18–3.85 (m, 3H), 3.78–3.52 (m,2H), 2.70 (s, 1H), 2.58–2.39 (m, 1H), 1.62–0.62 (m, 22H)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) and (3-phenylpyrrolidin-3-yl)carbamicacid tert-butyl ester (Example A30) using General Method B.

(xx){7-[3-(tert-Butoxycarbonylaminomethyl)-4-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (MS ES: m/z 582 (MH⁺)) from(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14) andtrans-(4-methylpyrrolidin-3-yl)carbamic acid tert-butyl ester (KuniyoshiM., Seigo S., Keiji H., Takayoshi I., Eur. Pat. Appl., 1987, EP 208210)using general procedure F.

EXAMPLE 9 Deprotection of Quinazolin-2,4-diones

General Method A

Hydrogen chloride gas is bubbled into diethyl ether (or dichloromethaneor dichloroethane for 15 minutes. The resulting solution is then cooledto 0° C. and added to a solution of a2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester(Example 6), The reaction mixture is slowly warmed to room temperature.After 30 hours, the precipitate is filtered, washed with ether (ordichloromethane or dichloroethane) and hexanes, and dried under vacuumto afford the hydrochloride salt of the desired deprotected amine as asolid.

General Method B

A compound is dissolved in trifluoroacetic acid and stirred at 0° C. for3 to 8 hours. The acid is removed by blowing compressed air over thesolution or concentrate in vacuo. The residue is twice co-evaporatedwith ethanol and dried in vacuo to yield the trifluoroacetate salt ofthe title compound as a solid.

General Method C

A3-dibenzylamino-6-fluoro-1-substituted-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester and 20% Pd/C (cat.) are combined in methanol andshaken under 50 psi of hydrogen for 22.5 hours. The suspension isfiltered through Celite and concentrated. The residue is purified viachromatography (SiO₂, CHCl₃) to give a solid. The solid is thendissolved in methylene chloride, cooled to 0° C., and HCl gas is passedthrough the solution for 10 minutes. The suspension is stirred for 2hours and concentrated to give the title compound.

General Method D

Hydrogen chloride gas is bubbled through a solution of substrate indiethyl ether, and the solution stirred for 2 hours. The solvent isremoved under reduced pressure to afford the desired title compound as asolid.

General Method E

A solution of substrate in ethanol is treated with a solution of ethanolsaturated with gaseous hydrogen chloride. The reaction mixture isstirred at room temperature for 18 hours, and the solvent is removed invacuo. The residue is dissolved in water, filtered through a fiber glasspad to clarify, and lyophilized. The solid residue is triturated withether, filtered, washed with ether and dried in vacuo.

General Method F

A solution of3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b), 1.2 eq. of heterocyclic amine side chain, and 1:3N,N-diisopropylethylamine/acetonitrile is heated at 50° C. for 18 hours.The reaction mixture is diluted with water, cooled to 0° C., and thesolid is removed by filtration, washed with 50% aqueous acetonitrile,and dried in vacuo to give a solid that is dissolved in ethanol andtreated with a solution of ethanol saturated with gaseous hydrogenchloride. The mixture is then stirred at room temperature for 18 hours.The solvent is removed in vacuo and the residue is triturated withether. The solid is removed by filtration, washed with ether and driedin vacuo.

The following compounds are synthesized according to General ProceduresA–F of Example 9:

(a)3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 1) (mp 153–155° C., MS CI: m/z 368 (MH⁺)) from7-[3-(tert-butoxycarbonylamino-methyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8a) using General Method A.

(b)3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-piperazin-1-yl-1H-quinazoline-2,4-dionehydrochloride (Compound 2) (mp 156–159° C., MS CI: m/z 354 (MH⁺)) from7-[4-(tert-butoxycarbonylpiperazin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8b) using General Method A.

(c)3-Amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 3) (mp 166–168° C., MS CI: m/z 382 (MH⁺)) from{7-[3-(tert-butoxycarbonylamino-methyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8c) using General Method A.

(d)3-Amino-7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-2,4-dionehydrochloride (Compound 4) (mp 111–114° C., MS CI: m/z 366 (MH⁺)) from[7-(6-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8d) using General Method A.

(e)3-Amino-7-((S)-3-N-methylaminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 5) (mp 118–120° C., MS CI: m/z 368 (MH⁺)) from{7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8e) using General Method A.

(f)3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-8-chloro-1-(2,4-difluoroanilino)-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 6) (mp 184–186° C., MS CI: m/z 427 (MH⁺)) from{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-(2,4-difluoroanilino)-6-fluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8f) using General Method A.

(g)3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-6,8-difluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 7) (mp 288° C. (dec.), MS EI: m/z 338 (M⁺)) from7-[(S)-3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropylamino-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8g) using General Method A.

(h)3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 8) (mp 338° C. (dec), MS EI: m/z 338 (M⁺)) from{7-[(S)-3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8h) using General Method A

(i)3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-5,6,8-trifluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 9) (mp 271° C. (dec.), MS CI: m/z 356 (MH⁺))from{7-[(S)-3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (Example 8i) using General Method A.

(j)3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 10) (mp 134–136° C., MS CI: m/z 354 (MH⁺)) from{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8a) using General Method A.

(k)7-((S)-3-Aminopyrrolidin-1-yl)-1-cyclopropyl-3,5-diamino-6,8-difluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 11) (mp 215–218° C. (dec.), MS EI: 352 (M⁺))from{5-amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 12) using Method A.

(l)3-Amino-7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 12) (mp 78–80° C., MS CI: m/z 369 (MH⁺)) from[7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8k) using Method A.

(m)3-Amino-7-(3-aminoethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 13) (mp 158–160° C., MS CI: m/z 382 (M⁺)) from{7-[3-(tert-butoxycarbonylamino-ethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 81) using Method A.

(n)3-Amino-7-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 14) (mp 177–179° C., MS CI: m/z 380 (MH⁺) from[7-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8m) using General Method A.

(o)3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 15) (mp 117–120° C., MS CI: m/z 396 (MH⁺)) from{7-[(R)-3-(1-tert-butoxycarbonylamino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8n) using General Method A.

(p)3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 16) (mp 170–172° C., MS CI: m/z 334 (MH⁺)) from{7-[3-(tert-butoxycarbonylamino-methyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8o) using General Method A.

(q)3-Amino-7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 17) (mp 96–98° C., MS CI: m/z 339 (MH⁺)) from[7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8p) using General Method A.

(r)3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-6-fluoro-1-isopropyl-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 18) (mp 151° C., MS EI: m/z 356 (M⁺)) from{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-8-chloro-6-fluoro-1-isopropyl-2,4-dioxo-6-fluoro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8q) using General Method B.

(s)3-Amino-7-(3-aminopyrrolin-1-yl)-1-sec-butyl-8-chloro-6-fluoro-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 19) (mp 115° C.) from{7-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-sec-butyl-8-chloro-6-fluoro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8r) using General Method B.

(t)3-Amino-7-[3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 20) (mp 216–218° C., MS EI: m/z 350 (MH⁺)) from{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8s) using Method A.

(u)3-Amino-7-[3-aminopyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 21) (mp 205–208° C. (dec.), MS EI: m/z 368(MH⁺)) from{7-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8t) using General Method A.

(v)3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 22) (mp 210–212° C., MS EI: m/z 320 (M+))from{7-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-8-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8u) using Method A.

(w)3-Amino-7-(3-aminopyrrolidin-1-yl)-6-chloro-1-cyclopropyl-8-fluoro-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 23) (mp 135–137° C., MS EI: m/z 354 (MH⁺))from{7-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-6-chloro-1-cyclopropyl-8-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8v) using General Method B.

(x)3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropylmethyl-8-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 24) (mp>250° C., MS CI: m/z 334 (MH⁺)) from[(S)-1-(1-cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 8w) using General Method C.

(y)3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropylmethyl-8-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 25) (mp>250° C., MS CI: m/z 376 (MH⁺)) from{1-[(R)-1-(cyclopropylmethyl-3-dibenzylamino-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl)carbamicacid tert-butyl ester (Example 8x) using General Method C.

(z)-3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-ethyl-8-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 26) (mp 248–251° C., MS CI: m/z 308 (MH⁺)) from[(S)-1-(3-dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-carbamicacid tert-butyl ester (Example 8y) using General Method C.

(aa)3-Amino-1-ethyl-6-fluoro-7-[(R)-3-(1-amino-1-methylethyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dionehydrochloride (Compound 27) (mp>250° C., MS CI: m/z 350 (MH⁺)) from[(R)-1-(3-dibenzylamino-1-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-1-methyl-1-pyrrolidin-3-ylethyl]carbamicacid tert-butyl ester (Example 8z) using Method C.

(bb)3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 28) (mp>250° C., MS CI: m/z 320 (MH⁺)) from3-amino-{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione(Example 25) using General Method A.

(cc)3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 29) (mp 110–112° C., MS ES, MH⁺) m/z 334)from[7-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8aa) using General Method B.

(dd)3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 30) (mp 82–84° C., MS ES, m/z 348 (M⁺)) from{7-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8bb) using General Method B.

(ee)3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 31) (mp 208–210° C., MS ES, m/z 350 (MH⁺)) from[7-(3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8 cc) using General Method A.

(ff)3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 32) (mp 180–182° C., MS ES, m/z 364 (MH⁺)) from{7-[3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester (Example 8dd) using General Method A.

(gg)3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 33) (mp 220° C., MS ES, m/z 364 (MH⁺)) from[7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8ee) using General Method A.

(hh)3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-carbonitrilehydrochloride (Compound 34) (mp 277° C., MS ES, m/z 345 (MH⁺)) from[7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-8-cyano-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8ff) using General Method A.

(ii)3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)-1H-quinazoline-2,4-dionetrifluoroacetate (Compound 35) (mp 145–147° C., MS ES, m/z 406 (MH⁺))from[8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8gg) using General Method B.

(jj)3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 36), (mp 215–217° C.) from{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamicacid tert-butyl ester (Example 28a) using General Method E.

(kk)3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 37) (mp 221–223° C.) from{(S)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamicacid tert-butyl ester (Example 28b) using General Method A.

(ll)3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 38) (mp 197–199° C.) from{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl]pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28c) using General Method E.

(mm)3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 39) (mp 192–194° C.) from{(S)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-ethyl}carbamicacid tert-butyl ester (Example 28d) using General Method E.

(nn)5-Amino-9-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dionehydrochloride (Compound 40) (mp 202–204° C.) from[(S)-1-(5-amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,5-diazaphenalen-9-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28e) using General Method E.

(oo)5-Amino-9-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-fluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dionehydrochloride (Compound 41) (mp 192–194° C.) from{(S)-1-[(R)-1-(5-amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,5-diazaphenalen-9-yl)-pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28f) using General Method E.

(pp)2-Amino-8-((S)-3-aminopyrrolidin-1-yl)-9-fluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione,hydrochloride (Compound 42) (mp 202–204° C.) from[(S)-1-(2-amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28g) using General Method E.

(qq)2-Amino-8-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-9-fluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dionehydrochloride (Compound 43) (mp 197–199° C.) from{(R)-3-[(S)-1-(2-amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)-pyrrolidin-3-yl}ethyl]carbamicacid tert-butyl ester (Example 28h) using General Method E.

(rr)3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 44) (mp 213–215° C.) from[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28i) using General Method E.

(ss)3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione,hydrochloride (Compound 45) (mp 268–270° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and 3-azabicyclo[3.1.0]hex-6-ylcarbamic acid tert-butylester using General Method F.

(tt)3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione,hydrochloride (Compound 46) (mp 187–189° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and [1-methyl-(3-methylpyrrolidin-3-yl)]methylcarbamicacid tert-butyl ester (J. Med. Chem., 1992; 361–367) using GeneralMethod F.

(uu)3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-c]pyridin-2-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 47) (mp 200–203° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and (3aS,7aR)-octahydropyrrolo[3,4-c]pyridine-5-carboxylicacid tert-butyl ester (Example A27) using General Method F.

(vv)3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-b]pyridin-2-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 48) (mp 200–202° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and octahydropyrrolo[3,4-b]pyridine-5-carboxylic acidtert-butyl ester using General Method F.

(ww)3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 49) (mp>260° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and (R)-3-(1-amino-1-methylethyl)-pyrrolidine usingGeneral Method F.

(xx)3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione,dihydrochloride(Compound 50) (mp 152–154° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example 24b) and(3-aminomethylpiperidin-1-yl)carbamic acid tert-butyl ester (Hilpert K.et al., J. Med. Chem., 1994; 37[23]:3889–3901) using General Method F.

(yy)trans-3-Amino-7-(3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 51) (mp 214–216° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and 3-aminomethyl-4-trifluoromethylpyrrolidine (Li Q.,Wang W., Berst K. B., Claiborne A., Hasvold L., Raye K., Tufano M., etal., Bioorg. Med. Chem. Lett., 1998; 8:1953–1958) using General MethodF.

(zz)3-Amino-1-cyclopropyl-6-fluoro-7-[(R)-3-((R)-1-methylamino-ethyl)pyrrolidin-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 52) (mp 137–139° C.) from3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b) and (R)-3-((R)-1-methylaminoethyl)pyrrolidine usingGeneral Method F.

(aaa)3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dionehydrochloride (Compound 53) (mp>260° C.) from{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]-ethyl}carbamicacid tert-butyl ester (Example 28j) using General Method E.

(bbb)3-Amino-7-[3-(1-aminopropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 54) (MS CI: m/z 376 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]propyl}carbamicacid tert-butyl ester (Example 28ooo) using General Method E.

(ccc)3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dionehydrochloride (Compound 55) (mp 153–5° C.) from{(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-ethyl}methylcarbamicacid tert-butyl ester (Example 28 ppp) using General Method E.

(ddd)3-Amino-7-[7-(1-aminoethyl)-5-azaspiro[2,4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 56) (mp 178–80° C., MS CI: m/z 388 (MH⁺)) from{1-[5-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-aza-spiro[2.4]hept-7-yl]-ethyl}carbamicacid tert-butyl ester (Example 28qqq) using General Method E.

(eee)1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidine-3-carboxylicacid amide (Compound 58) (mp 141–144° C., MS CI: m/z 396 (MH⁺)) from[7-(3-carbamoylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-carbamicacid tert-butyl ester using General Method A (Example 8hh).

(fff)3-Amino-[7-trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 59) (mp 171–173° C., MS CI: m/z 436 (MH⁺)) from{7-[trans-3-(tert-butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8ii) using General Method E.

(ggg)3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-{3-[(2,2,2-trifluoro-ethylamino)methyl]pyrrolidin-1-yl}-1H-quinazoline-2,4-dionehydrochloride (Compound 60) (mp 163–164° C., MS CI: m/z 450 (MH⁺)) from8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-7-{3-[(2,2,2-trifluoroethylamino)methyl]-pyrrolidin-1-yl}-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 8jj) using General Method E.

(hhh)3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-1H-quinazoline-2,4-dionehydrochloride (Compound 61) (mp 133–1355° C., MS CI: m/z 394 (MH⁺)) from[8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8kk) using General Method E.

(iii)3-Amino-8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-1H-quinazoline-2,4-dione(Compound 62) (mp 147–149° C., MS CI: m/z 394 (MH⁺)) from[8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8ll) using General Method E.

(jjj)3-Amino-7-(3-aminomethyl-3-benzylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 63) (mp 148–150° C., MS CI: m/z 458 (MH⁺)) from(7-[3-benzyl-3-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester (Example 8 mm) using General Method E.

(kkk)3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 64) (mp 164–166° C., MS CI: m/z 382 (MH⁺)) from{7-[(R)-3-((S)-1-tert-butoxycarbonylaminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8nn) using General Method E.

(lll)3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyimino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione(Compound 65) (mp 147–9° C., MS CI: m/z 368 (MH⁺)) from)[8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyimino-pyrrolidin-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8oo) using General Method E.

(mmm)3-Amino-7-[trans-3-amino-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 66) (mp 181–183° C., MS CI: m/z 422 (MH⁺)) from[7-(trans-3-tert-butoxycarbonylamino-4-trifluoromethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8 pp) using General Method E.

(nnn) 3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[(R)-3-(S)1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dionehydrochloride (Compound 67) (mp 122–124° C., MS CI: m/z 396 (MH⁺)) from(7-{(R)-3-(S)-1-(tert-butoxycarbonylmethylamino)ethyl]pyrrolidin-1-yl}-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 8qq) using General Method E.

(ooo)3-Amino-7-(trans-3-amino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 68) (mp 174–175° C., MS CI: m/z 430 (MH⁺)) from[7-(trans-3-tert-butoxycarbonylamino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 8rr) using General Method E.

(ppp)3-Amino-7-[trans-3-amino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride. (Compound 69) (mp>200° C., MS CI: m/z 446 (MH⁺)) using7-[trans-3-tert-butoxycarbonylamino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8ss) and General Method E.

(qqq)N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamidehydrochloride (Compound 70) (mp 109–112° C., MS CI: m/e 446 (M⁺)) from{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)-pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 36) using General Method E.

(rrr)3-Amino-7-(3-aminomethylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 71) (mp 131–133° C., MS CI: m/z 382 (MH⁺)) from{7-[3-(tert-butoxycarbonylaminomethyl)piperidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 8tt) using General Method E.

(sss)3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[3-(isopropylamino-methyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dionehydrochloride (Compound 72) (mp 125–127° C., MS CI: m/z 410 (MH⁺)) from(7-{3-[(tert-butoxycarbonyl-isopropylamino)methyl]pyrrolidin-1-yl}-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 8uu) using General Method E.

(ttt)3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-6,8-dichloro-1-cyclopropyl-1H-quinazoline-2,4-dionehydrochloride (Compound 73) (mp 147–149° C., MS CI: m/z 384 (MH⁺)) from{7-[3-(tert-butoxycarbonylaminomethyl)-pyrrolidin-1-yl]-6,8-dichloro-1-cyclopropyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester using General Method E.

(uuu)N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide(Compound 74) (mp 109–112° C., MS CI: m/z 446 (MH⁺)) from{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Example 36) using General Method E.

(vvv)3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 75) (mp 194–196° C., ¹H NMR (200 MHz, DMSO-d₆):δ 8.25 (bs, 3H), 7.47 (d, 1H), 4.68 (bs, 3H), 3.59–3.23 (m, 7H), 2.49(s, 3H), 2.02–1.92 (m, 1H), 1.80–1.60 (m, 1H), 1.30 (d, 3H), 1.12–1.08(m, 2H), 0.62–0.50 (m, 2H); MS ES: m/z 362 (MH⁺)) from{1-[1-[(R)-3-(S)-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28k) using General Method A.

(www)3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 76) (mp 200–202° C., MS ES: m/z 376 (MH⁺)) from{1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl}carbamicacid tert-butyl ester (Example 28l) using Method A.

(xxx)3-Amino-7-[3-(1-aminoethyl)-3-methoxypyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 77) (mp 190–192° C., ¹H NMR (200 MHz, DMSO-d₆):δ 8.07 (bs, 3H), 7.49 (d, 1H), 3.89–3.10 (m, 121H), 2.42 (s, 3H),2.39–2.08 (m, 2H), 1.29 (d, 3H), 1.07–1.03 (m, 2H), 0.62–0.52 (m, 2H);MS ES: m/z 392 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methoxypyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28m) using General Method A.

(yyy)3-Amino-7-[3-(1-aminoethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 78) (mp 190–192° C., MS ES: m/z 396 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-fluoropyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28o) using General Method A.

(zzz)3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 79) (mp 238–240° C., MS ES: m/z 334 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28p) using General Method A.

(aaaa)3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 80) (mp 245–247° C., MS ES: m/z 362 (MH⁺)) from{1-(S)-[1-(R)-(3-amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28q) using General Method A.

(bbbb)3-Amino-7-(3-aminomethyl-3-methoxymethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 81) (mp 172–177° C., MS ES: m/z 392 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methoxymethylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28r) using General Method A.

(cccc)3-Amino-7-(3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 82) (mp 160–163° C., MS ES: m/z 380 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-fluoromethylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28s) using General Method A.

(dddd)3-Amino-7-(trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 83) (mp 205–207° C., MS ES: m/z 432 (MH⁺)) from[trans-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-trifluoromethyllpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28t) using General Method A.

(eeee)3-Amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 84) (mp 198° C., MS ES: m/z 392 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28u) using General Method A.

(ffff)3-Amino-7-[3-(aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 85) (mp 200° C., ¹H NMR (200 MHz, DMSO-d₆): δ8.25 (bs, 3H), 7.52 (d, 1H), 6.36 (bs, 3H), 3.54–2.80 (m, 6H), 2.48 (s,3H), 2.02–1.15 (m, 8H), 1.02–0.50 (m, 4H); MS ES: m/z 376 (MH+)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-yl]ethyl}carbamicacid tert-butyl ester Example 28v) using General Method A.

(gggg)3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 86) (mp 230° C., MS ES: m/z 406 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28w) using General Method A.

(hhhh)3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride. (Compound 87) (mp 246° C., MS ES: m/z 390 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28×) using General Method A.

(iiii)3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 88) (mp 236° C., MS ES: m/z 410 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-phenylpyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28z) using General Method A.

(jjjj)3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 89) (mp 240° C., MS ES: m/z 376 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28y) using General Method A.

(kkkk)3-Amino-7-(3-aminomethyl-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 90) (mp 227–231° C., MS ES: m/z 424 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)3-phenylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28aa) using General Method A.

(llll)3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 91) (mp 167° C., MS ES: m/z 374 (MH⁺)) from[5-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamicacid tert-butyl ester (Example 28bb) using General Method A.

(mmmm)3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 92) (mp 178° C., MS ES: m/z 390 (MH⁺)) from[5-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamicacid tert-butyl ester (Example 28 cc) using General Method A.

(nnnn)3-Amino-7-(3-aminomethyl-3-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 93) (mp 202° C., MS ES: m/z 380 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-hydroxypyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28dd) using General Method A.

(oooo)3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 95) (mp 219–221° C., MS ES: m/z 362 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28ee) using General Method A.

(pppp)3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 96) (mp>250° C., MS ES: m/z 364 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28ff) using General Method A.

(qqqq)3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 97) (mp>250° C., MS ES: m/z 380 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28gg) using General Method A.

(rrrr)3-Amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 98) (mp>250° C., MS ES: m/z 368 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28hh) using General Method A.

(ssss)3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 99) (mp 210° C., MS ES: m/z 362 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28ii) using General Method A.

(tttt) 3-Amino-7-[(R)-3(-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-ethyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 100) (mp 155–157° C., MS ES: m/z 376 (MH⁺)) from{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-8-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28jj) using General Method A.

(uuuu)1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid trifluoroacetate (Compound 101) (mp 252° C. (decomp), MS ES: m/z379 (MH⁺)) from1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid tert-butyl ester (Example 28kk) using General Method B.

(vvvv)1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid trifluoroacetate (Compound 102) (mp 226° C. (decomp), MS ES: m/z363 (MH+)) from1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid tert-butyl ester (Example 28ll) using General Method A.

(wwww)3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 103) (mp 183–185° C., MS ES: m/z 376 MH⁺)) from[3-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamicacid tert-butyl ester (Example 28 mm) using General Method A.

(xxxx)3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 104) (mp 189–194° C., MS ES: m/z 360 (MH⁺)) from[3-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamicacid tert-butyl ester (Example 28nn) using General Method A.

(yyyy)3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 105) (mp 175–179° C., MS ES: m/z 378 (MH⁺)) from{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28oo) using General Method A.

(zzzz)3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 106) (mp 172–176° C., MS (ES: m/z 362 (MH⁺))from{(R)-1-[(S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28 pp) using General Method A.

(aaaaa) 3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(octahydropyrrolo[3,4-b]pyridin-6-yl)-1H-quinazoline-2,4-dione hydrochloride (Compound107) (mp 220° C., MS ES: m/z 374 (MH⁺)) from6-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)octahydropyrrolo[3,4-b]pyridine-1-carboxylicacid tert-butyl ester (Example 28qq) using General Method A.

(bbbbb)3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 108) (mp 215–217° C., MS ES: m/z 382 (MH+)) from{7-[trans-3-(tert-butoxycarbonyl-aminomethyl)-4-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (Compound 109) (Example 8xx) using General MethodA.

(ccccc)3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 110) (mp 189° C., MS ES: m/z 378 (MH+)) from[trans-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28rr) using General Method A.

(ddddd)3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 111) (mp 220° C., MS ES: m/z 362 (MH⁺)) from[trans-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28ss) using General Method A.

(eeeee)3-Amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 112) (mp 209° C., MS ES: m/z 364 (MH⁺)) from[trans-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]carbamicacid tert-butyl ester (Example 28tt) using General Method A.

(fffff)3-Amino-7-(3-aminomethylmorpholin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 113) (mp 195° C., MS ES: m/z 380 (MH⁺)) from[4-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)morpholin-2-ylmethyl]carbamicacid tert-butyl ester (Example 28uu) using General Method A.

(ggggg)3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 114) (mp 201° C., MS ES: m/z 378 (MH⁺)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-ylmethyl]-carbamicacid tert-butyl ester (Example 28vv) using General Method A.

(hhhhh)3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 115) (mp 204.5° C., MS ES: m/z 392 (MH⁺)) from{1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28ww) using General Method A.

(iiiii)3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dionehydrochloride (Compound 116) (mp 198–200° C., MS ES: m/z 430 (MH⁺)) from[7-(3-tert-butoxycarbonylamino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]carbamicacid tert-butyl ester (Example 6ww) using General Method A.

(jjjj)3-Amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 117) (mp 237–240° C., MS ES: m/z 348 (MH⁺)) from[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methylpyrrolidin-3-yl]]carbamicacid tert-butyl ester (Example 28xx) using General Method A.

(kkkkk)3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1yl-1H-quinazoline-2,4-dionehydrochloride (Compound 118) (mp 178–180° C., MS ES: m/z 319 (MH⁺)) from3-amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione(Example 28yy) using General Method A.

(lllll)3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1yl-1H-quinazoline-2,4-dionehydrochloride (Compound 119) (mp 92–94° C., MS ES: m/z 335 (MH⁺)) from3-amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione(Example 28zz) using General Method A.

(mmmmm)3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 120) (mp 116–120° C., MS ES: m/z 377 (MH⁺)) from3-amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione (Example 28aaa) usingGeneral Method E.

(nnnnn) 3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione hydrochloride(Compound 121) (mp 134° C. (decomp), MS ES: m/z 393 (MH⁺)) from3-amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione (Example 28bbb)using General Method E.

(ooooo)3-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dionehydrochloride (Compound 122) (mp 182–185° C., MS ES: m/z 376 (MH⁺)) from{(S)-1-[(R)-3-amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione(Example 28 ccc) using General Method E.

(ppppp)(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 123) (mp 185–190° C., MS ES: m/z 406 (MH+)) from(S)-1-[(R)-1-(3-amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 28ddd) using General Method E.

(qqqqq)3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 124) (mp 210–215° C., MS ES: m/z 390 (MH⁺)) from3-amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione(Example 28eee) using General Method E.

(rrrrr)3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 125) (mp>190° C., MS ES: m/z 390 (MH⁺)) from3-amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 28fff) using General Method E.

(sssss)3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 126) (mp 201° C., MS ES: m/z 378 (MH+)) from3-amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 28hhh) using General Method E.

(ttttt)3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 127) (MS ES: m/z 350 (MH⁺)) from3-amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 28ggg) using General Method E.

(uuuuu)cis-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 128) (mp 169–179° C., MS ES: m/z 382 (MH+)) fromcis-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28iii) using General Method A.

(vvvvv)trans-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 129) (mp 144–147° C., MS ES: m/z 382 (MH⁺)) fromtrans-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (Example 28jjj) using General Method A.

(wwwww)3-Amino-7-(1-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 130) (mp>250° C., MS APCI: m/z 376 (MH+)) from[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-(1-amino-5-azaspiro[2.4]hept-5-yl)]carbamicacid tert-butyl ester (Example 28kkk) using General Method A.

(xxxxx)3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 131) (mp>250° C., MS APCI: m/z 418 (MH+)) from1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-aminomethyloctahydroisoindol-2-yl]carbamicacid tert-butyl ester (Example 28lll) using General Method A

(yyyyy)3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 132) (mp>250° C., MS APCI: m/z 402 (MH⁺)) from1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-aminomethyloctahydroisoindol-2-yl]carbamicacid tert-butyl ester (Example 28 mmm) using General Method A

(zzzzz)3-Amino-7-[(R)-3-((S)-1-aminoethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dionehydrochloride (Compound 133) (mp 228–230° C., MS APCI: m/z 378 (MH⁺))from{(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (Example 28nnn) using General Method E

(aaaaaa)3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dionehydrochloride (Compound 134) (mp 180–182° C., MS ES: m/z 346 (MH⁺)) from[3-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamicacid tert-butyl ester (Example 28n) using General Method A.

EXAMPLE 10 Synthesis of{7-[(S)-3-(tert-butoxycarbonylamino)pyrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester

A solution of{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-1,4-dihydro-2,4-dioxo-5,6,8-trifluoro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester from Example 8 (0.51 g, 0.914 mmol), triethylamine(1.3 mL, 9.3 mmol), and benzylamine (0.50 mL, 4.6 mmol) in dimethylsulfoxide (7.5 mL) is heated at 100° C. for 16 hours in a sealed glasstube. The mixture is concentrated under high vacuum and the residuepurified by column chromatography (1:2 ethyl acetate/hexanes) to afford{7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester as a solid (0.51 g). ¹NMR (CDCl₃): δ 8.50 (bs,1H), 7.37–7.18 (m, 5H), 6.56 (bs, 1H), 4.76–4.62 (bd, 1H), 4.59–4.48 (m,2H), 4.34–4.18 (m, 1H), 3.93–3.49 (m, 3H), 3.48–3.20 (m, 2H), 2.24–2.04(m, 1H), 1.96–1.74 (m, 1H), 1.49 (s, 9H), 1.46 (s, 9H), 1.13–1.00 (m,2H), 0.75–0.61 (m, 2H).

EXAMPLE 11 Synthesis of{7-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-methylcarbamicacid tert-butyl ester

To a solution of{7-[(S)-3-(tert-butoxycarbonyl-N-methylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester from Example 8 (0.238 g, 0.421 mmol) inN,N-dimethylformamide (5 mL) at −78° C. under nitrogen atmosphere isadded sodium hydride (60% dispersion in mineral oil, 0.025 g, 0.631mmol). After 30 minutes, iodomethane (0.052 mL, 0.842 mmol) is added,and the reaction mixture is warmed to room temperature. After 1 hour,the reaction mixture is diluted with ethyl acetate and washed withsaturated ammonium chloride solution, water, and brine. The organiclayer is dried over MgSO₄, filtered, and the filtrate concentrated. Theresulting residue is purified by flash column chromatography (1:1 ethylacetate/hexanes) to afford the title compound (0.118 g). ¹H NMR (CDCl₃):δ 7.63 (dd, 1H), 4.78 (bs, 1H), 3.87–3.45 (m, 6H), 2.62–2.44 (m, 6H),2.31–2.12 (m, 2H), 1.49–1.47 (m, 18H), 1.23–1.07 (m, 2H), 0.75–0.53 (m,2H). MS CI: m/z 582 (MH⁺).

EXAMPLE 12 Synthesis of{5-Amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester

{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamicacid tert-butyl ester from Example 10 (0.435 g, 0.676 mmol) intetrahydrofuran (20 mL) is hydrogenated at room temperature andatmospheric pressure over 20% palladium hydroxide on carbon (0.114 g)for 27 hours. The mixture is filtered through Celite, the solid iswashed with chloroform, and the combined filtrates concentrated undervacuum. Purification by column chromatography (2:3 ethylacetate/hexanes) gives{5-amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamicacid tert-butyl ester as a solid (0.284 g). ¹H NMR (CDCl₃): δ 6.61 (bs,1H), 5.94 (bs, 2H), 4.82–4.69 (bd, 1H), 4.40–4.21 (m, 1H), 4.00–3.59 (m,3H), 3.55–3.41 (m, 1H), 3.35–3.21 (m, 1H), 2.32–2.08 (m, 1H), 2.01–1.80(m, 1H), 1.50 (s, 9H), 1.46 (s, 9H), 1.17–1.01 (m, 2H), 0.77–0.63 (m,2H).

EXAMPLE 13 Synthesis of8-Chloro-1-cyclopropyl-6-fluoro-3-methylamino-7-[(S)-3-methylaminopyrrolidin-1-yl]-1H-quinazolin-2,4-dione

Hydrogen chloride gas is bubbled into diethyl ether (30 mL) for 15minutes. The resulting solution is then cooled to 0° C. and added to{7-[(S)-3-(tert-butoxycarbonylmethylamino)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}methyl-carbamicacid tert-butyl ester from Example 11 (0.118 g, 0.202 mmol). Thereaction mixture is slowly warmed to room temperature. After 30 hours,the precipitate is filtered, washed with ether and hexanes, and driedunder vacuum to afford the hydrochloride salt of the title compound as asolid (0.0632 g, mp 77–79° C.). MS CI: m/z 382 (MH⁺).

EXAMPLE 14 Synthesis of(8-Chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester

To a solution of(3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl)-hydrazinecarboxylicacid tert-butyl ester (Example 6c) (1.93 g, 5.34 mmol) intetrahydrofuran (50 mL) is added potassium carbonate (3.69 g, 26.7 mol)and triphosgene (2.06 g, 6.95 mmol). The reaction mixture is refluxedfor 90 minutes, cooled to room temperature, and diluted with ethylacetate. The organic layer is washed with water and brine, then driedover MgSO₄ and filtered. The filtrate is concentrated under vacuum andpurified via flash column chromatography (1:2 ethyl acetate/hexanes) toafford the title compound (1.27 g). MS EI: m/z 386 (M⁺).

EXAMPLE 15 Synthesis of 2-Amino-4,5-difluorobenzoic acid,2,2-dibenzylhydrazide

4,5-Difluoroanthranilic acid (4.73 g, 27.3 mmol) andN,N-dibenzylhydrazine (8.69 g, 42 mmol) are combined in 200 mL ofmethylene chloride. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDAC) (7.85 g, 41 mmol) is then added to this solution,and the mixture is stirred for 18 hours at 25° C., The solution iswashed with saturated NaHCO₃, brine, and dried over magnesium sulfate.The solution is concentrated to give 15.8 g of a dark oil and purifiedvia chromatography (SiO₂, CHCl₃) to give 3.4 g of the title compound asa solid. MS CI: m/z 368 (MH⁺).

EXAMPLE 16 Synthesis of3-Dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione

2-Amino-4,5-difluorobenzoic acid, 2,2-dibenzylhydrazide (Example 15)(0.81 g, 2.2 mmol) and triphosgene (0.33 g, 1.1 mmol) are combined in100 mL of methylene chloride and stirred at 25° C. for 20 hours. Thesolution is poured into 200 mL of saturated NaHCO₃, the layers areseparated, and the aqueous layer is washed three times with ethylacetate. The combined organic layers are dried over magnesium sulfateand then concentrated to give 0.86 g of the title compound as a solid.MS CI: m/z 394 (MH⁺).

EXAMPLE 17 Synthesis of3-Dibenzylamino-6,7-difluoro-1-substituted-1H-quinazoline-2,4-dione (a)3-Dibenzylamino-6,7-difluoro-1-cyclopropylmethyl-1H-quinazoline2,4-dione

A solution of 3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione(Example 16) (0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide isadded to a suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL ofN,N-dimethylformamide and stirred for 30 minutes.Bromomethylcyclopropane (0.16 mL, 1.6 mmol) is added, and the mixture isstirred at 25° C. for 18 hours. The reaction is quenched with 1 mL ofwater and concentrated in vacuo. The residue is dissolved in chloroform,washed with water, brine, and dried over magnesium sulfate. The solutionis concentrated and purified via chromatography (SiO₂, CHCl₃) to give0.33 g of the title compound as a solid. MS CI: m/z 448 (MH⁺).

(b) 3-Dibenzylamino-6,7-difluoro-1-ethyl-1H-quinazoline-2,4-dione

A solution of 3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione(Example 16) (0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide isadded to a suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL ofN,N-dimethylformamide and stirred for 30 minutes. Ethyl iodide (0.13 mL,1.6 mmol) is added, and the mixture is stirred at 25° C. for 18 hours.The reaction is quenched with 1 mL of water and concentrated in vacuo.The residue is dissolved in chloroform, washed with water, brine, anddried over magnesium sulfate. The solution is concentrated and purifiedvia chromatography (SiO₂, CHCl₃) to give 0.34 g of the title compound asa solid, mp 133–135° C., MS CI, m/z 422 (MH⁺).

EXAMPLE 18 Chlorination

General Chlorination Method

To a solution of a benzoylhydrazinecarboxylic acid tert-butyl ester(Example 7) in acetic acid (5 mL) is added N-chlorosuccinimide (1.2eq.). After 1 hour, the reaction mixture is diluted with ethyl acetateand washed with saturated NaHCO₃, water, and brine. The organic layer isdried over MgSO₄ and filtered. The filtrate is concentrated under vacuumand purified via flash column chromatography (ethyl acetate/hexanes) toafford the corresponding chloro-benzoylhydrazinecarboxylic acidtert-butyl ester.

The following compounds are synthesized according to the GeneralChlorination Method above:

(a)N′-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 542 (MH⁺)) fromN′-{4-[3-(tert-butoxycarbonylamino-methyl)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 7a).

(b).N′-4-[4-(tert-Butoxycarbonylpiperazin-1-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 528 (MH⁺)) fromN′-4-[4-(tert-butoxycarbonylpiperazin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 7b).

(c)N′-{4-[3-(tert-Butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 556 (MH⁺)) fromN′-{4-[3-(tert-butoxycarbonylaminomethyl)-3-methylpyrrolidin-1-yl]-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7c).

(d)N′-[4-(6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 540 (MH⁺)) fromN′-[4-(6-tert-butoxycarbonylamino-3-aza-bicyclo[3.1.0]hex-3-yl)-2-cyclopropylamino-5-fluorobenzoyl]-hydrazinecarboxylicacid tert-butyl ester (Example 7d).

(e)N′-{4-[(S)-3-(tert-Butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS CI: m/z 542 (MH⁺)) fromN′-{4-[(S)-3-(tert-butoxycarbonyl-N-methylamino)pyrrolidin-1-yl]-2-cyclopropylamino-5-fluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 7e).

(f)N′-{4-[(S)-3-(tert-Butoxycarbonyl-N-amino)pyrrolidin-1-yl]-3-chloro-2-(2,4-difluoroanilino)-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (CDCl₃): δ 9.70 (bs, 1H), 7.76 (d, 1H), 6.93–6.82(m, 1H), 6.70–6.62 (m, 2H), 6.48–6.34 (m, 2H), 4.91–4.87 (bs, 1H),4.29–4.20 (m, 1H), 3.78–3.60 (m, 2H), 3.50–3.28 (m, 2H), 2.33–2.20 (m,1H), 1.94–1.66 (m, 1H), 1.44 (s, 9H), 1.42 (s, 9H), (MS CI: m/z 601(MH⁺)) fromN′-{4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(2,4-difluoroanilino)-5-fluorobenzoyl}-hydrazinecarboxylicacid tert-butyl ester (Example 7f).

(g)N′-[4-((S)-7-tert-Butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl)-3-chloro-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (MS CI: 554 (MH⁺)) fromN′-[(S)-4-(7-tert-butoxycarbonylamino-5-aza-spiro[2.4]hept-5-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylicacid tert-butyl ester (Example 7k).

(h)N′-[4-(Pyrrolidin-1-yl)-3-chloro-2-cyclopropylamino-5-fluoro-benzoyl]hydrazinecarboxylictert-butyl ester (MS CI: m/z 413 (MH⁺)) fromN′-[4-(pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoyl]hydrazinecarboxylictert-butyl ester (Example 7m).

(i)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl)-3-chloro-5-fluoro-2-isopropylaminobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS: m/z 530 (MH⁺)) fromN′-{4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-fluoro-2-isopropylaminobenzoyl}hydrazinecarboxylic acid tert-butyl ester (Example 7 n).

(j)N′-{4-[3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclobutylamino-3-chloro-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (MS EI: m/e 542 (MH⁺)) fromN′-{4-[3-(tert-butoxycarbonylamino)-pyrrolidin-1-yl]-2-cyclobutylamino-5-fluorobenzoyl}hydrazinecarboxylicacid tert-butyl ester (Example 7q).

(k)N′-(1-{4-[3-(tert-Butoxycarbonylamino-methyl)piperidin-1-yl]-3-chloro-2-cyclopropylamino-5-fluorophenyl}methanoyl)hydrazinecarboxylicacid tert-butyl ester (MS CI: m/e 556 (MH⁺)) fromN′-(1-{4-[3-(tert-butoxycarbonylaminomethyl)piperidin-1-yl]-2-cyclopropylamino-5-fluoro-phenyl}methanoyl)hydrazinecarboxylicacid tert-butyl ester (Example 7z).

(l)N′-[1-(4-{3-[(tert-Butoxycarbonylisopropylamino)methyl]-pyrrolidin-1-yl}-3-chloro-2-cyclopropylamino-5-fluorophenyl)methanoyl]-hydrazine-carboxylicacid tert-butyl ester (MS CI: m/e 584 (MH⁺)) fromN′-[1-(4-{3-[(tert-butoxycarbonylisopropylamino)methyl]pyrrolidin-1-yl}-2-cyclopropylamino-5-fluorophenyl)methanoyl]hydrazinecarboxylicacid tert-butyl ester (Example 7aa).

(m)N′-(1-{4-[3-(tert-Butoxycarbonylaminomethyl)pyrrolidin-1-yl]-3,5-dichloro-2-cyclopropylaminophenyl}methanoyl)hydrazinecarboxylicacid tert-butyl ester (MS CI: m/e 558 (MH⁺)) fromN′-(1-{4-[3-(tert-butoxycarbonylamino-methyl)pyrrolidin-1-yl]-5-chloro-2-cyclopropylaminophenyl}methanoyl)-hydrazinecarboxylicacid tert-butyl ester (Example 7bb).

EXAMPLE 19 Chlorination of Substituted Benzoic Acids (a) Synthesis of3-Chloro-4,5-difluoroanthranilic acid

To a solution of 4,5-difluoroanthranilic acid (2.45 g, 14.2 mmol) indichloromethane (25 mL) is added acetic acid (10 mL) and hypochlorousacid tert-butyl ester (1.75 mL, 15.6 mmol). After 2 hours, the reactionmixture is diluted with ethyl acetate and washed with water and brine.The organic layer is dried over MgSO₄, filtered, and concentrated. Theresulting residue is purified via flash column chromatography (5%isopropyl alcohol/1% formic acid/94% dichloromethane) to afford3-chloro-4,5-difluoroanthranilic acid as an oil (2.97 g). MS CI: m/z 206(M⁺).

(b) 5-Chloro-4-fluoroanthranilic acid

To a solution of 4-fluoroanthranilic acid (0.882 g, 5.69 mmol) inmethylene chloride (50 ML) and acetic acid (10 mL) is added tert-butylhypochlorite (0.71 mL, 6.25 mmol) solution in dichloromethane (1 mL)dropwise over 1 minute. After 90 minutes, the reaction mixture is washedwith water and brine. The organic layer is dried over MgSO₄, filtered,and the filtrate concentrated to afford 5-chloro-4-fluoroanthranilicacid (1.20 g). MS CI: m/e 188 (M⁺).

EXAMPLE 20 Synthesis of 2-Bromo-3-chloro-4,5-difluorobenzoic acid

A solution of cuprous bromide (10.96 g, 49.2 mmol)) in acetonitrile (100mL) is cooled to 0° C. and then tert-butyl nitrite (7.31 mL, 61.5 mmol)and 3-chloro-4,5-difluoroanthranilic acid (Example 19) (8.51 g, 41.0mmol) are added. The mixture is slowly warmed to room temperature, andafter 20 hours, the solvent is removed under vacuum. The resultingresidue is dissolved in ethyl acetate and washed with 1.0 M hydrochloricacid, water, and brine. The organic layer is dried over MgSO₄ andfiltered. The filtrate is concentrated under vacuum and purified viaflash column chromatography (5% isopropyl alcohol/1% formic acid/94%dichloromethane) to afford 2-bromo-3-chloro-4,5-difluorobenzoic acid asa solid (7.96 g). MS CI: m/z 271 (MH⁺).

EXAMPLE 21 Synthesis of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic acidethyl ester

To a solution of4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic acidethyl ester (Example 2h) (3.50 g, 9.50 mmol) in dichloromethane (80 mL)is added acetic acid (8 mL) and tert-butyl hypochlorite (1.75 mL, 15.6mmol). After 20 minutes, the reaction mixture is diluted with ethylacetate and washed with water and brine. The organic layer is dried oversodium sulfate, filtered, and the filtrate concentrated. The resultingresidue is purified by column chromatography (1:4 ethyl acetate/hexanes)to afford the title compound (3.75 g) as an oil. ¹H NMR (CDCl₃): δ 7.69(dd, 1H), 4.85–4.76 (bd, 1H), 4.50–4.20 (m, 3H), 3.90–3.74 (m, 2H),3.62–3.36 (m, 2H), 2.40–2.20 (m, 1H), 1.91–1.84 (m, 1H), 1.45 (s, 9H),1.40 (s, 9H).

EXAMPLE 22 Synthesis of 2-cyclopropylamino-4,5-difluorobenzoic acidmethyl ester

To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid (Example5a) (6.0 g, 28.1 mmol), dichloromethane (100 mL), and methanol (20 mL)is added (trimethylsilyl)diazomethane (2.9 M solution in hexane)dropwise until the evolution of gas stops. The solution is stirred atroom temperature for 0.5 hour and 88% formic acid is added dropwiseuntil the evolution of gas again stops. Water is added, and the solutionis extracted with dichloromethane, dried over MgSO₄, filtered, and thesolvent removed under reduced pressure. The residue is purified bysilica gel column chromatography using hexane/EtOAc (9:1) as the eluentto afford a 5.4 g of the title compound as a clear oil. MS CI: m/z 228(MH⁺).

EXAMPLE 23 (a) Synthesis of1-Cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione

To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid ethyl ester(Example 22) (5.0 g, 22.0 mmol) in dry dichloromethane (120 mL) under aN₂ atmosphere is added chlorosulfanyl isocyanate (3.11 g, 22 mmol). Thesolution is reacted at room temperature for 4 hours, and the solvent isremoved under reduced pressure. The residue is cooled to −20° C., and acold brine solution (100 mL) buffered with NaHCO₃ is added. The solutionis warmed to room temperature for 1 hour. The volume is reduced by halfwith a stream of air, and the solid is collected by filtration. The drysolid is added to a solution of triethylamine (5 mL) in THF (250 mL) andrefluxed overnight. The reaction is cooled, the solvent removed underreduced pressure, dissolved in water (100 mL), and acidified to pH 1–2with 1.0 M hydrochloric acid. The resulting precipitate is collected viafiltration to afford 2.0 g of the title compound. MS CI: m/z 239 (MH⁺).

(b) 1-Cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione

A solution of 1-cyclopropyl-3-(3-methoxy-2,4,5-trifluorobenzoyl)urea(Example 27b, 0.94 g, 3.26 mmol) in tetrahydrofuran (20 mL) andN,N-dimethylformamide (5 mL) is treated with sodium hydride (0.275 g,6.8 mmol, 60% in mineral oil dispersion) and heated at reflux for 16hours. The mixture is cooled, treated with saturated NH₄Cl and extractedwith dichloromethane. The organic layer is then washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. Flash columnchromatography (1:3 ethyl acetate/hexanes) afforded the title compound.MS (EI, M+1) m/z 269.

(c) Synthesis of8,9-Difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diaza-phenalene-4,6-dione

A solution of 1.5 g (6.2 mmol) of7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acidmethyl ester (Example 32a) in 25 mL of dichloromethane is cooled to −20°C. and treated dropwise with 0.92 g (6.5 mmol) of chlorosulfonylisocyanate. The reaction is stirred at room temperature for 18 hours andthe solvent removed in vacuo. The residue is treated with a saturatedsodium bicarbonate solution and extracted with dichloromethane. Theorganic layer is dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue is dissolved in 50 mL of tetrahydrofuran, and the resultingsolution is treated with 5.0 g (5.0 mmol) of triethylamine. Afterheating at reflux for 4 hours, the solvent is removed in vacuo, and theresidue is triturated with 5 mL of dichloromethane/ethyl acetate(80:20). The insoluble material is removed by filtration, washed withthe above solvent mixture (2 mL) to give 0.25 g of the title compound,mp 259–261° C. The filtrate is chromatographed over flash grade silicagel (230–400 mesh) eluting with dichloromethane/ethyl acetate (80:20) togive 0.38 g of starting material. Continued elution afforded anadditional 0.2 g of the title compound. ¹H NMR (400 MHz, CDCl₃): 11.78(s, 1H), 7.50 (m, 1H), 4.68 (m, 1H), 4.52 (d, 1H), 4.17 (d, 1H), 1.23(d, 3H).

(d) Synthesis of8,9-Difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione

A solution of 1.07 g (4.4 mmol) of5,6-difluoro-2-methyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acidmethyl ester (Example 32) in 25 mL of dichloromethane is cooled to −20°C. and treated dropwise with 0.85 g (6.0 mmol) of chlorosulfonylisocyanate. The reaction is stirred at −20° C. for 1 hour, treated with1.0 g (12 mmol) of solid sodium acetate, and the solvent is removed invacuo. The residue is cooled in an ice bath and triturated with asaturated solution of sodium acetate in brine. The precipitate isremoved by filtration, washed with the sodium acetate solution and driedin vacuo. The dried precipitate is washed with ether to remove startingmaterial and dried in vacuo. The dried solid is suspended in 40 mL ofdry tetrahydrofuran, cooled to 5° C. and treated portionwise with 1.2 g(12 mmol) of sodium tert-butoxide. After the addition is complete, thereaction mixture is stirred at 5° C. for 30 minutes, the bath isremoved, and the reaction is stirred to room temperature over 1 hour.The solvent is removed in vacuo; the residue is dissolved in water,cooled to 5° C. and acidified with formic acid. The resultingprecipitate is removed by filtration, washed with water and dried invacuo affording 0.8 g of the title compound, mp 212–214° C.

(e)1-Cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione

A solution of 4.1 g (15.2 mmol) of ethyl2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34) in125 mL of dichloromethane is cooled to −20° C. and treated dropwise with5.24 g (37 mmol) of chlorosulfonyl isocyanate. The reaction is stirredat −20° C. for 3 hours and allowed to come to room temperatureovernight. The mixture is recooled to −20° C. and treated with 6.8 g (80mmol) of solid sodium acetate. After stirring for 1 hour withoutcooling, the solvent is removed in vacuo without heating. The residue istriturated with a saturated solution of sodium acetate in brine andextracted with ethyl acetate (3×75 mL). The combined organic layers aredried (MgSO₄), filtered and evaporated in vacuo. The residue issuspended in 100 mL of tetrahydrofuran and treated with 3.6 g (32 mmol)of solid sodium tert-butoxide and stirred at room temperature for 36hours. The solvent is removed in vacuo, the residue triturated with 100mL of 0.1 M formic acid and extracted with ethyl acetate (3×100 mL). Thecombined organic layers are washed with water, dried (MgSO₄), filteredand evaporated in vacuo to give a residue which is chromatographed overflash grade silica gel (230–400 mesh) eluting with dichloromethane togive 0.75 g of the title compound, mp 220–222° C.

General Procedure A

Sodium hydride (3 eq., 60% mineral oil dispersion) is added portionwiseto a solution of 1-cyclopropyl-3-benzoylurea (Example 27) in 20:1tetrahydrofuran/N,N-dimethylformamide at −25° C. The mixture is stirredat room temperature for 30 minutes, then refluxed overnight. It ispoured into ice water, and the solution is acidified with 10%hydrochloric acid and extracted with ethyl acetate. The extract iswashed with brine, dried, and concentrated. The residue is purified bysilica gel column chromatography (ethyl acetate/hexanes) to afford8-substituted 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-diones.

The following compounds are synthesized according to General Procedure Aof Example 23:

(e) 1-Cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione (¹H NMR(200 MHz, CDCl₃): δ 8.61 (bs, 1H), 7.83 (dd, 1H), 3.37–3.35 (m, 1H),2.60 (dd, 3H), 1.31–1.12 (m, 2H), 0.71–0.63 (m, 2H) from1-cyclopropyl-3-(2,4,5-trifluoro-3-methylbenzoyl)urea (Example 27c).

(f) 1-Cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione (¹H NMR(200 MHz, CDCl₃): δ 8.37 (bs, 1H), 7.96 (dd, 1H), 2.81–2.74 (m, 1H),2.61 (d, 3H), 1.2.6–1.14 (m, 2H), 0.81–0.73 (m, 2H)) from1-cyclopropyl-3-(3,4,6-trifluoro-2-methylbenzoyl)urea (Example 27d).

(g) 1-cyclopropyl-6,7-difluoro-8-ethyl-1H-quinazoline-2,4-dione (¹H NMR(200 MHz, CDCl₃): δ 9.41 (bs, 1H), 7.86–7.77 (m, 1H), 3.40–3.20 (m, 3H),1.30–1.10 (m, 5H), 0.75–0.67 (m, 2H)) from1-cyclopropyl-3-(3-ethyl-2,4,5-trifluorobenzoylurea (Example 27e).

(i) 7-Chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(mp 214–216° C.) from1-cyclopropyl-3-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)urea (Example27a).

EXAMPLE 24 (a) Synthesis of3-Amino-1-cyclopropyl-6,7-difluoro-]H-quinazoline-2,4-dione

To a solution of 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione(Example 23a, 2.0 g, 8.92 mmol) in dioxane (7.5 mL) anddimethylformamide (7.5 mL) is added NaH (60% dispersion in oil, 428 mg,10.7 mmol). The solution is heated to 60° C. for 10 minutes and cooledto room temperature. To the cooled solution is addedO-(2,4-dinitrophenyl)hydroxylamine (1.77 g, 8.92 mmol), and the solutionis heated to 80° C. for 30 minutes. The resulting red solution is cooledto room temperature, poured over crushed ice, and extracted with EtOAc.The combined organic layers are dried over MgSO₄, filtered, and thesolvent removed under reduced pressure. The resulting solid istriturated with Et₂O and air dried to afford 1.44 g of the titlecompound. MS CI: m/z 254 (MH⁺).

(b)3-Amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione

A solution of 3.83 g (15 mmol) of7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 23i) in 50 mL of dimethylformamide-dioxane (1:1) is cooled to0° C. and treated portionwise with 0.8 g (20 mmol) of 60% sodiumhydride/mineral oil. The reaction is stirred to room temperature for 30minutes, re-cooled to 0° C. and 3.2 g (16 mmol) of2,4-dinitrophenylhydroxylamine is added all at once. After stirring atroom temperature overnight, the dioxane is removed in vacuo and theresidue is diluted to 300 mL with ice and water and stirred at 5° C. for1 hour. The precipitate is removed by filtration, washed with water,ether and dried in vacuo to give 2.65 g of the title compound, mp192–194° C. A second crop, (0.6 g) could be isolated by evaporating thefiltrate and triturating the residue with petroleum ether.

(c)3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonicacid

A solution of 0.47 g (1.57 mmol) of1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonicacid (Example 35) in 20 mL of dimethylformamide/dioxane (1:1) is treatedportionwise with 0.08 g (2.0 mmol) of 60% sodium hydride/mineral oil.The reaction is stirred at room temperature for 1 hour and 0.32 g (1.6mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. Afterstirring at room temperature overnight, the dioxane is removed in vacuoand the residue is diluted to 100 mL with ice and water and stirred at5° C. for 1 hour. The aqueous solution is extracted with ethyl acetate(3×50 mL) with the combined organic layers being washed with water,dried (MgSO₄), filtered and evaporated in vacuo to give 0.4 g of thetitle compound, mp 167–169° C.

General Procedure A (Example 24)

To a solution of a 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione(Example 23) in 1:1 dry tetrahydrofuran or dioxane and dryN,N-dimethylformamide is added portionwise sodium hydride (1.1 eq., 60%mineral oil dispersion) at room temperature. After stirring at 50° C.for 20 to 30 minutes, the resulting solution is cooled to roomtemperature and 2,4-dinitrophenylhydroxylamine (4 eq.) is added. Themixture is heated at 60° C. to 80° C. for 30 minutes, cooled, and thedioxane removed reduced pressure. The residue is poured into ice waterand extracted with ethyl acetate. The organic layers are combined,washed with brine, dried with Na₂SO₄, and concentrated in vacuo. Theresidue is purified by flash column chromatography (ethylacetate/hexanes) to afford a3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione.

The compounds are synthesized according to General Procedure A ofExample 24:

(d)3-Amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(MS EI: m/z 284 (MH⁺)) from1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione (Example23b).

(e) 3-Amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ 7.86 (dd, 1H), 5.20 (bs, 2H), 3.48–3.38 (m,1H), 2.61 (dd, 3H), 1.29–1.17 (m, 2H), 0.73–0.62 (m, 2H)) from1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione (Example23e).

(f) 3-Amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ 7.45 (dd, 1H), 5.28 (bs, 2H), 2.94–2.83 (m,1H), 2.77 (d, 3H), 1.41–1.31 (m, 2H), 0.98–0.93 (m, 2H)) from1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione (Example23f).

(g) 3-Amino-1-cyclopropyl-6,7-difluoro-8-ethyl-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ 7.84–7.75 (t, 1H), 5.37 (bs, 2H), 3.50–3.40(m, 1H), 3.37–3.21 (m, 2H), 1.29–1.15 (m, 5H), 0.75–0.66 (m, 2H)) from1-cyclopropyl-6,7-difluoro-8-ethyl-1H-quinazoline-2,4-dione (Example23g).

(h)5-Amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diaza-phenalene-4,6-dione(mp 171–173° C.) from8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diaza-phenalene-4,6-dione(Example 23c).

(i)2-Amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione,mp 140–142° C., ¹H NMR (400 MHz, CDCl₃): 7.90 (m, 1H), 5.30 (bs, 2H),5.07 (m, 1H), 3.08 (m, 1H), 2.85 (m, 1H), 2.15 (m, 1H), 1.95 (m, 1H),1.31 (d, 3H)) from8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione(Example 23d).

EXAMPLE 25 Synthesis of{3-Amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione

To a solution of3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example24a) (50.0 mg, 0.20 mmol) and triethylamine (74 mg, 0.74 mmol) inacetonitrile (3 mL) is added (S)-pyrrolidin-3-yl carbamic acidtert-butyl ester (74 mg, 0.40 mmol). The solution is refluxed for 18hours, the solvent is removed under reduced pressure, and the residuetriturated with water. The solid is collected by filtration and airdried to afford 74 mg of the title compound. MS CI: m/z 420 (MH⁺).

EXAMPLE 26 Synthesis of Benzamides

General Procedure A

A solution of an appropriately substituted benzoic acid, oxalyl chloride(1.5 eq.), and dichloromethane is treated with N,N-dimethylformamide (2drops), the solution is stirred at room temperature for 2 hours. Themixture is concentrated under reduced pressure, and the residue isdissolved in dry THF and slowly added to a solution of ammonia indiethyl ether at −70° C. The mixture is then allowed to warm to ambienttemperature and stirred for 30 minutes. The mixture is then filtered andthe resulting solid dissolved in ethyl acetate, washed with water, anddried over Na₂SO₄. The solvent is then concentrated in vacuo to providethe desired amide.

The following compounds are synthesized according to the GeneralProcedure A method above:

(a) 3,4,6-Trifluoro-2-methylbenzamide. (¹H NMR (200 MHz, CDCl₃): δ6.89–6.77 (m, 1H), 6.41 (bs, 1H), 5.95 (bs, 1H), 2.39 (d, 3H)) from3,4,6-trifluorobenzoic acid (Hagen S. et al., Heterocycl. Chem., 1990;27[6]:1609–1616).

(b) 3-Ethyl-2,4,5-trifluorobenzamide, (¹H NMR (200 MHz, CDCl₃): δ7.78–7.60 (m, 1H), 6.61 (bs, 2H), 2.67 (q, 2H), 1.15 (t, 3H)) from3-ethyl-2,4,5-trifluorobenzoic acid (Takemura, PCT Int. Appl., 1996, WO9623782).

EXAMPLE 27 Synthesis of 1-cyclopropyl-3-benzoyl substituted ureas (a)1-Cyclopropyl-3-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl) urea

A solution of 5.8 g (27.8 mmol) of 2,6-dichloro-5-fluoronicotinamide(Chem. Pharm. Bull., 1987; 35:2280) in 60 mL of dichloromethane istreated dropwise with 5.1 g (40 mmol) of oxalyl chloride, and thereaction mixture is heated at reflux for 18 hours. The solvent isremoved in vacuo, and the residue is dissolved in 50 mL ofdichloromethane, which is also removed in vacuo. The residue isdissolved in 50 mL of dichloromethane, cooled to −20° C. and treateddropwise with 2.28 g (40 mmol) of cyclopropylamine. The reaction mixtureis stirred at −20° to −10° C. for ½ hour, then allowed to come to roomtemperature over 2 hours. The solvent is removed in vacuo and theresidue is triturated with 25 mL of dichloromethane, which is alsoremoved in vacuo to give 8.0 g of the title compound, mp 171–173° C.

General Procedure A

To a solution of substituted benzamide (Example 26) in1,2-dichloroethane is added oxalyl chloride (1.5 eq.) and the mixturerefluxed for 16 hours. The solvent is then removed under reducedpressure to obtain a crude isocyanate. The isocyanate is then taken upinto dioxane, cooled to 0° C. and treated with cyclopropylamine (1.5eq.) in dioxane. The mixture is then warmed to ambient temperature andstirred for 3 hours. The mixture is then concentrated under reducedpressure, dissolved in ethyl acetate, washed with water, dried overNa₂SO₄ and evaporated under reduced pressure. The resulting residue isthen purified by flash column chromatography (ethyl acetate/hexanes) toafford the 1-cyclopropyl-3-benzoyl urea.

The following compounds are synthesized according to the GeneralProcedure A method above:

(b) 1-Cyclopropyl-3-(2,4,5-trifluoro-3-methoxy-benzoyl)urea (MS ES(MH⁺): m/z 289) from 2,4,5-trifluoro-3-methoxybenzamide (Masuzawa K.,Suzue S., Hirai K., Ishizaki T., Eur. Pat. Appl., 1987, EP 230295).

(c) 1-Cyclopropyl-3-(2,4,5-trifluoro-3-methylbenzoyl)urea (¹H NMR (200MHz, CDCl₃): δ 8.69 (d, 1H), 8.48 (bs, 1H), 7.75–7.62 (m, 1H), 2.83–2.71(m, 1H), 2.30 (dd, 3H), 0.87–0.78 (m, 2H), 0.67–0.59 (m, 2H)) from2,4,5-trifluoro-3-methylbenzamide (Masuzawa K., Suzue S., Hirai K.,Ishizaki T., Eur. Pat. Appl., 1987, EP 237955).

(d) 1-Cyclopropyl-3-(3,4,6-trifluoro-2-methylbenzoyl)urea (¹H NMR (200MHz, CDCl₃): δ 8.99 (bs, 1H), 8.37 (bs, 1H), 6.93–6.80 (m, 1H),2.74–2.65 (m, 1H), 2.35 (d, 3H), 0.84–0.71 (m, 2H), 0.66–0.58 (m, 2H))from 3,4,6-trifluoro-2-methylbenzamide (Example 26a).

(e) 1-Cyclopropyl-3-(3-ethyl-2,4,5-trifluorobenzoyl)urea (¹H NMR (200MHz, CDCl₃): δ 8.76–8.69 (bd, 1H), 8.50 (bs, 1H), 7.76–7.63 (m, 1H),2.84–2.72 (m, 3H), 1.27–1.20 (m, 3H), 0.91–0.81 (m, 2H), 0.71–0.61 (m,2H)) from 3-ethyl-2,4,5-trifluorobenzamide (Example 26b).

EXAMPLE 28 (a) Synthesis of{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamicacid tert-butyl ester

A solution of 0.57 g (2.0 mmol) of3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d), 0.64 g (3.0 mmol) of((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het.Chem., 1992; 29:1481), 0.81 g (8.0 mmol) of triethylamine and 10 mL ofdimethyl sulfoxide is heated at 110° C. for 4 hours. The reactionmixture is cooled to room temperature, poured into 150 mL of ice andwater, and extracted with ethyl acetate (2×125 mL). The combined organiclayers are washed with water, dried (MgSO₄), filtered and evaporated invacuo to give 1.1 g of crude product. Chromatography on flash gradesilica gel (230–400 mesh) eluting with dichloromethane/ethanol (9:1)provided 0.92 g of the title compound, mp 96–98° C.

(b) Synthesis of{(S)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl-pyrrolidin-3-yl]ethyl}-carbamicacid tert-butyl ester

A solution of 0.57 g (2.0 mmol) of3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d), 0.64 g (3.0 mmol) of((S)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J Het.Chem., 1992; 29:1481), 0.81 g (8.0 mmol) of triethylamine, and 10 mL ofdimethyl sulfoxide is heated at 110° C. for 4 hours. The reactionmixture is cooled to room temperature, poured into 150 mL of ice andwater and extracted with ethyl acetate (2×125 mL). The combined organiclayers are washed with water, dried (MgSO₄), filtered and evaporated invacuo to give 1.08 g of crude product. Chromatography on flash gradesilica gel (230–400 mesh) eluting with dichloromethane/ethanol (9:1)provided 0.9 g of the title compound, mp 87–89° C.

(c) Synthesis of{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-carbamicacid tert-butyl ester

A solution of 0.5 g (1.9 mmol) of3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e), 0.64 g (3.0 mmol) of((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester, 0.81 g(8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at110° C. for 24 hours. After thin layer chromatography showed incompletereaction, an additional 0.43 g (2.0 mmol) of pyrrolidine derivative and0.81 g (8.0 mmol) of triethylamine are added and the reaction is heatedat 120° C. for 18 hours. The reaction mixture is cooled to roomtemperature, poured into 200 mL of ice and water and extracted withethyl acetate (2×125 mL). The combined organic layers are washed withwater, dried (MgSO₄), filtered and evaporated in vacuo to give 1.1 g ofcrude product. Chromatography on flash grade silica gel (230–400 mesh)eluting with ethyl acetate provided 0.4 g of the title compound, mp86–88° C.

(d) Synthesis of{(S)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamicacid tert-butyl ester

A solution of 0.5 g (1.9 mmol) of3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e), 0.64 g (3.0 mmol) of((S)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester, 0.81 g(8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at110° C. for 24 hours. After thin layer chromatography showed incompletereaction, an additional 0.43 g (2.0 mmol) of pyrrolidine derivative and0.81 g (8.0 mmol) of triethylamine are added and the reaction is heatedat 120° C. for 18 hours. The reaction mixture is cooled to roomtemperature, poured into 200 mL of ice and water and extracted withethyl acetate (2×125 mL). The combined organic layers are washed withwater, dried (MgSO₄), filtered and evaporated in vacuo to give 1.3 g ofcrude product. Chromatography on flash grade silica gel (230–400 mesh)eluting with 400 mL of dichloromethane/ethyl acetate (8:2), 600 mL of(6:4) and 1 L of (4:6) provided 0.46 g of the title compound, mp 84–86°C.

(e) Synthesis of[(S)-1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,5-diazaphenalen-9-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

A solution of 0.2 g (0.75 mmol) of5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione(Example 24h), 0.58 g (2.0 mmol) of (S)-3-pyrrolidinylcarbamic acidtert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.5 g (0.5 mmol) oftriethylamine and 20 mL of acetonitrile is heated at reflux for 18hours. The solvent is removed in vacuo and the residue is partitionedbetween dichloromethane-water. The organic layer is washed with water,dried (MgSO₄) and concentrated in vacuo. The residue is chromatographedover flash grade silica gel (230–400 mesh) eluting withdichloromethane/ethanol (95:5) to give 0.34 g of the title compound, mp114–116° C.

(f){(S)-1-[(R)-1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,5-diazaphenalen-9-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester

A solution of 0.11 g (0.41 mmol) of5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione(Example 24h), 0.26 g (1.3 mmol) of((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het.Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and 10 mL ofacetonitrile is heated at reflux for 18 hours. The solvent is removed invacuo and the residue is partitioned between ethyl acetate/water. Theorganic layer is washed with water, dried (MgSO₄) and concentrated invacuo. The residue is chromatographed over flash grade silica gel(230–400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.14g of the title compound. ¹H NMR (400 MHz, CDCl₃): 7.43 (d, 1H), 5.24(bs, 2H), 4.82 (m, 1H), 4.56 (m, 1H), 4.33 (d, 1H), 3.99 (m, 1H), 3.86(m, 1H), 3.73 (m, 1H), 3.59 (m, 2H), 2.18 (m, 1H), 3.01 (m, 1H), 1.67(m, 1H), 1.44 (s, 9H), 1.40 (m, 3H), 1.25 (m, 1H), 1.20 (d, 3H).

(g)[(S)-1-(2-Amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester

A solution of 0.12 g (0.45 mmol) of5-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione(Example 24i), 0.34 g (1.8 mmol) of (S)-3-pyrrolidinylcarbamic acidtert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.2 g (2.0 mmol) oftriethylamine and 7 mL of dimethyl sulfoxide is heated at 110° C. for 18hours. The reaction is cooled to room temperature, diluted with 80 mL ofice and water and stirred at 5° C. for 1 hour. The resulting precipitateis removed by filtration, washed with water and dried in vacuo. Thesolid is chromatographed over flash grade silica gel (230–400 mesh)eluting with dichloromethane/ethanol (9:1) to give 0.14 g of the titlecompound, mp 98–100° C.

(h){(R)-3-[(S)-1-(2-Amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-y}ethylcarbamicacid tert-butyl ester

A solution of 0.12 g (0.45 mmol) of5-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione(Example 24i), 0.39 g (1.8 mmol) of((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het.Chem., 1992; 29:1481), in 5 mL of dimethyl sulfoxide is heated at 110°C. for 18 hours. The reaction is cooled to room temperature, dilutedwith 80 mL of ice and water and stirred at 5° C. for 1 hour. Theresulting precipitate is removed by filtration, washed with water anddried in vacuo. The solid is chromatographed over flash grade silica gel(230–400 mesh) eluting with dichloromethane/ethanol (9:1) to give 0.13 gof the title compound, mp 93–95° C.

(i)[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester

A solution of 0.11 g (0.4 mmol) of3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 24b), 0.105 g (0.56 mmol) of (S)-3-pyrrolidinylcarbamic acidtert-butyl ester (J. Med. Chem., 1992; 35:1764), 1.2 mL ofN,N-diisopropylethylamine and 3 mL of acetonitrile is heated at 50° C.for 18 hours. The reaction mixture is diluted with 9 mL of water, cooledto 0° C. and the solid is removed by filtration, washed with 50% aqueousacetonitrile and dried in vacuo to give 0.14 g of the title compound, mp108–110° C.

(j){(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethyl}-carbamicacid tert-butyl ester

A solution of 0.12 g (0.38 mmol) of3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonicacid (Compound 24c) in 10 mL of acetonitrile is treated with 0.24 g(1.14 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butylester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamineand stirred at room temperature for 18 hours then 50° C. for 1 hour. Thesolvent is removed in vacuo and the residue is partitioned between ethylacetate (50 mL) and water (25 mL). The organic layer is washed withwater, dried (MgSO₄), filtered and evaporated in vacuo to give 0.28 g.Chromatography on flash grade silica gel (230–400 mesh) column (2×12 cm)eluting with dichloromethane/ethanol (95:5) provided 0.1 g of the titlecompound, mp 175–177° C.

General Procedure A

A solution of Example 24, 1–2.5 eq of heterocyclic amine side chain, and3–3.5 eq. 1,8-diazabicyclo-5,4,0-undecen-7-ene (DBU) or triethylamineare stirred in dimethyl sulfoxide (1 mL) at 130° C. for 3 to 48 hours.After cooling to room temperature, the reaction mixture is diluted withethyl acetate and washed with saturated NaHCO₃, water, and brine. Theorganic layer is dried over MgSO₄, filtered, and the filtrateconcentrated. The resulting residue is purified via flash columnchromatography (isopropanol/dichloromethane) to afford the product.

General Procedure B

A solution of Example 24 and heterocyclic diamine side chain (1.5–3.0eq.) is stirred in dimethyl sulfoxide at 130° C. for 3 hours. Aftercooling to room temperature the reaction mixture is diluted with ethylacetate and washed with saturated NaHCO₃, water, and brine. The organiclayer is; dried over MgSO₄, filtered, and the filtrate concentrated. Theresulting residue is redissolved in dichloromethane and while stirring,di-tert-butyl dicarbonate (0.41 g, 1.87 mmol) is added. After 1 hour,the reaction mixture is concentrated and the product is purified viaflash column chromatography (1:1 EtOAc/hexanes) to afford the product.

General procedure C

A solution of Example 24, heterocyclic diamine side chain (1.5–3.0 eq.)and tetramethyl guanidine (1–5.0 eq.) is stirred in dimethyl sulfoxideat (80° C.–130° C.) for 36 to 24 hours. After cooling to roomtemperature the reaction mixture is diluted with water and saturatedNH₄Cl. The solid is washed with water and dried to give the crude solid.The product is purified via flash column chromatography (SiO₂) using(CHCl₃/MeOH or ethyl acetate/hexanes) to afford the product.

The following compounds are synthesized according to the GeneralProcedures A, B, and C of Example 28:

(k){1-[(R)-1-((S)-3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 462 (MH+)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (R)-((S)-1-pyrrolidin-3-yl)ethylcarbamic acidtert-butyl ester (Kimura Y., Atarashi S., Takahashi M., Hayakkawa I.,Chem. Pharm. Bull., 1994; 42:1442) using General Method A.

(l){1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]-1-methylethyl}carbamicacid tert-butyl ester (MS ES: m/z 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and [(S)-(pyrrolidin-3-yl)-1-methylethyl]carbamic acidtert-butyl ester using General Method A.

(m){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methoxypyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 492 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and [1-(3-methoxypyrrolidin-3-yl)ethyl]carbamic acidtert-butyl ester (Example A5b) using General Method A.

(n)[3-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamicacid tert-butyl ester (MS ES: m/z 446 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 3-azabicyclo[3.1.0]hex-6-ylcarbamic acid tert-butylester (Brighty K. E., 1991, EP 413455) using General Method A.

(o){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-fluoropyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 496 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (4-fluoro-pyrrolidin-3-yl)ethylcarbamic acidtert-butyl ester (Example A5c) using General Method A.

(p)[1-(3-Amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]carbamicacid tert-butyl ester (MS ES: m/z 434 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione(Example 24f) and (pyrrolidin-3-yl)carbamic acid tert-butyl ester usingGeneral Method A.

(q){1-(R)-[1-(S)-(3-Amino-1-cyclopropyl-6-fluoro-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES:m/z 462 (MH+)) from3-amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione(Example 24f) and ((R)-((S)-1-pyrrolidin-3-yl-ethyl)amine using GeneralMethod A.

(r)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methoxymethylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 493 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (3-methoxymethylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (Example A5d) using General Method A.

(s)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-fluoromethylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.60 (d, 1H), 5.18(bs, 1H), 4.97 (bs, 2H), 4.61–4.10 (m, 4H), 3.72–3.19 (m, 5H), 2.46 (s,3H), 2.00–1.71 (m, 2H), 1.45 (s, 9H), 1.21–1.10 (m, 2H), 0.68–0.56 (m,2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 1-(3-fluoromethylpyrrolidin-3-ylmethyl]carbamic acidtert-butyl ester (Li Q., Wang W., Berst K. B., Claiborne A., Hasvold L.,Raye K., Tufano M., et al., Bioorg. Med. Chem. Lett., 1998; 8:1953–1958)using General Method A.

(t)[trans-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-trifluoromethylpyrrolidin-3ylmethyl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.56 (d, 1H), 5.17 (s,2H), 4.75 (bs, 1H), 3.97–3.68 (m, 3H), 3.57 (s, 3H), 3.51–3.13 (m, 4H),2.98–2.60 (m, 2H), 1.45 (s, 9H), 1.20–1.08 (m, 2H), 0.71–0.55 (m, 2H))from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and[trans-(4-trifluoromethylpyrrolidin-3-ylmethyl]carbamic acid tert-butylester (Li Q., Wang W., Berst K. B., Claiborne A., Hasvold L., Raye K.,Tufano M., et al., Bioorg. Med. Chem. Lett., 1998; 8:1953–1958) usingGeneral Method A.

(u){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS (ES, M+1) m/z 492 (M⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (1-piperidin-3-ylethyl)carbamic acid tert-butyl ester(Example A5e) using General Method A.

(v){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 1-(piperidin-3-yl)ethylcarbamic acid tert-butyl ester(Example A5e) using General Method A.

(w){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 506 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and [1-(4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic acidtert-butyl ester (Example A5f) using General Method A.

(x){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 490 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and [1-(4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic acidtert-butyl ester (Example A5f) using General Method A.

(y){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and [1-(4-methylpyrrolidin-3-yl)ethyl]carbamic acidtert-butyl ester (Example A5g) using General Method A.

(z)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-phenylpyrrolidin-3-yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.61 (d, 1H),7.50–7.12 (m, 5H), 5.19 (bs, 2H), 4.07–3.70 (m, 3H), 3.62–3.34 (m, 2H),2.68–2.52 (m, 1H), 2.45 (s, 3H), 1.68 (m, 2H), 1.50–0.95 (m, 11H), 0.62(m, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (3-phenylpyrrolidin-3-yl)carbamic acid tert-butylester (Example A30) (using General Method A).

(aa)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-phenylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.68 (d, 1H),7.50–7.29 (m, 5H), 6.72 (s, 1H), 5.24 (s, 2H), 4.18–3.85 (m, 3H),3.78–3.52 (m, 2H), 2.70 (s, 1H), 2.58–2.39 (m, 4H), 1.62–0.62 (m, 15H)from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (3-phenylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (Example A5p) using General Method A.

(bb)[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 474 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (5-azaspiro[2,4]hept-7-ylmethyl)carbamic acidtert-butyl ester (Example A5h) using General Method A.

(cc)[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-azaspiro[2.4]hept-7-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 490 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and 5-azaspiro[2,4]hept-7-ylmethyl)carbamic acidtert-butyl ester (Example A5h) using General Method A.

(dd)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-hydroxypyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 480 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (3-hydroxypyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (Example A5i) using General Method A.

(ee)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-ylmethyl]carbamicacid tert-butyl ester (REF) (MS ES: m/z 462 (MH+)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (piperidin-3-ylmethyl]carbamic acid tert-butyl ester(Hilpert K., Ackermann J., Banner D. W., Gast A., Gubernator K., HadvaryP., Labler L., et al., J. Med. Chem., 1994; 37[23]:3889–3901) usingGeneral Method A.

(ff)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.60–7.54 (d, 1H),5.16 (s, 2H), 4.82 (s, 1H), 4.20–3.85 (m, 5H), 3.42 (s, 3H), 3.23 (t,2H), 2.41 (s, 3H), 1.47 (s, 9H), 1.18–1.10 (m, 2H), 0.61 (s, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 4-(methoxypyrrolidin-3-yl)carbamic acid tert-butylester (Li Q., Cooper C. S., Anthony K. L., Lee C. M., Plattner J. J., MaZ., Wang W., 1996, WO 9639407) using Method A.

(gg)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methoxypyrrolidin-3-yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.21 (d, 1H),5.23–5.14 (m, 3H), 4.33–3.22 (m, 13H), 1.40 (s, 9H), 1.18 (m, 2H), 0.60(s, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and 4-(methoxypyrrolidin-3-yl)carbamic acid tert-butylester (Li Q., Cooper C. S., Anthony K. L., Lee C. M., Plattner J. J., MaZ., Wang W., 1996, WO 9639407) using Method A.

(hh)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, DMSO-d₆): δ 7.40–7.34 (d, 1H),5.30–4.80 (m, 3H) 4.50–3.10 (m, 10H), 1.47 (s, 9H), 1.30–0.50 (m, 4H))from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and 4-(fluoropyrrolidin-3-yl)carbamic acid tert-butylester (Li Q., Wang W., Berst K. B., Claiborne A., Hasvold L., Raye K.,Tufano M., et al., Bioorg. & Med. Chem. Lett., 1998; 8:1953–1958) usingGeneral Method A.

(ii)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 462 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (3-methylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (J. Med. Chem, 1992:361–367) using General Method A.

(jj){(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-8-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 476 (MH⁺)) from3-amino-1-cyclopropyl-8-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione(Example 24g) and ((R)-[(S)-1-pyrrolidin-3-yl-ethyl)ethyl]carbamic acidtert-butyl ester using General Method A.

(kk)1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.51 (d, 1H), 5.15 (s,2H), 3.88–3.58 (m, 4H), 3.50 (s, 3H), 3.42–3.30 (m, 1H), 3.14–3.02 (m,1H), 2.25–2.17 (m, 2H), 1.48 (s, 9H), 1.14–1.05 (m, 2H), 0.68–0.61 (m,2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and pyrrolidine-3-carboxylic acid tert-butyl ester(Hayakawa I., Tanaka Y., EP 101829) using General Method A.

(ll)1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.61 (d, 1H), 5.16 (s,2H), 3.70–3.40 (m, 5H), 3.17–3.03 (m, 1H), 2.43 (s, 3H), 2.29–2.19 (m,2H), 1.47 (s, 9H), 1.22–1.12 (m, 2H), 0.67–0.57 (m, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and pyrrolidine-3-carboxylic acid tert-butyl ester(Hayakawa I., Tanaka Y., EP 101829) using General Method A.

(mm)[3-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.53 (d, 1H), 5.31(bs, 2H), 4.73 (bs, 1H), 3.82–3.01 (m, 11H), 1.45 (s, 9H), 1.42–1.34 (m,1H), 1.14–1.10 (m, 3H), 0.71–0.63 (m, 2H)), from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (3-azabicyclo[3.1.0]hex-1-ylmethyl)carbamic acidtert-butyl ester (Example A5j) using General Method A.

(nn)[3-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-1-ylmethyl]yl]carbamicacid tert-butyl ester (MS ES: m/z 460) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (3-azabicyclo[3.1.0]hex-1-ylmethyl)carbamic acidtert-butyl ester (Example A5j) using General Method A.

(oo){(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 478 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (R)-1-((S)-pyrrolidine-3-yl)ethyl)carbamic acidtert-butyl ester (Schroeder M. C., Kiely J. S., Johnson D. R., Szotek D.L., Domagala J. M., Stickney T. M., Kampf J. W., J. Heterocyclic Chem.,1992; 29:1481) using General Method A.

(pp){(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester ¹H NMR (200 MHz, CDCl₃): δ 7.51–7.44 (d, 1H), 5.17(bs, 2H), 4.62 (bs, 0.5H), 4.58 (bs, 0.5H), 3.79–3.74 (m, 3H), 3.61–3.53(m, 2H), 3.49 (s, 3H), 3.41–3.32 (m, 1H), 2.22–2.06 (m, 2H), 1.87–1.67(m, 1H), 1.46 (s, 9H), 1.23–1.19 (d, 3H), 1.08–1.02 (m, 2H) 0.76–0.62(m, 2H).(MS ES: m/z 462) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (R)-1-((S)-pyrrolidine-3-yl)ethyl)carbamic acidtert-butyl ester using General Method A.

(qq)6-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)octahydropyrrolo[3,4-b]pyridine-1-carboxylicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.61–7.55 (d, 1H),5.16 (bs, 2H), 4.52 (bs, 0.5H), 4.48 (bs, 0.5H), 4.95–3.38 (m, 6H), 2.40(s, 3H), 2.36–1.83 (m, 3H), 1.46 (s, 9H), 1.21–1.17 (m, 5H), 0.65–0.57(m, 2H), from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and octahydropyrrolo[3,4-b]pyridine-5-carboxylic acidtert-butyl ester using General Method A.

(rr)[(trans)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 478 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (trans-4-methylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (Kuniyoshi M., Seigo S., Keiji H., Takayoshi I., Eur.Pat. Appl. EP 208210, 1987) using General Method A.

(ss)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 462 (MH+)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (4-methylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (Kuniyoshi M., Seigo S., Keiji H., Takayoshi I., Eur.Pat. Appl. EP 208210, 1987) using General Method A.

(tt)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]carbamicacid tert-butyl ester (MS ES: m/z 464 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (4-methylpyrrolidin-3-yl)carbamic acid tert-butylester (Di Cesare P., Bouzard D., Essiz M., Jacquet J. P., Ledoussai B.,Kiechet J. R., Remuzon P. et al., J. Med. Chem., 1992,35:4205) usingGeneral Method A.

(uu)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)morpholin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 480 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and I-(morpholin-3-ylmethyl)carbamic acid tert-butyl ester(Araki K., Kuroda T., Uemori S., Moriguchi A., Ikeda Y., Hirayama F.,Yokoyama Y. et al., J. Med. Chem., 1993,36:1356) using General Method A.

(vv)[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 478 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and 1-piperidin-3-ylmethylcarbamic acid tert-butyl ester(Hilpert K., et al., J. Med. Chem., 1994; 37(23):3889–3901) usingGeneral Method A.

(ww){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS ES: m/z 492 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and [1-(4-methylpyrrolidin-3-yl)ethyl]carbamic acidtert-butyl ester (A5g) using General Method A.

(xx)[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-methylpyrrolidin-3-yl]]carbamicacid tert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.61 (d, 1H), 5.15 (s,2H), 4.74 (s, 1H), 3.71–3.37 (m, 6H), 2.45–2.20 (m, 4H), 1.45 (s, 12H),1.21–1.08 (m, 2H), 0.61 (d, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 3-methylpyrrolidin-3-ylcarbamic acid tert-butyl ester(Yoshida T., Yamamoto Y., Orita H., Kakiuchi M., Takahashi Y., ItakuraM., Kado N. et al., Chem. Pharm. Bull., 1996; 44[7]:1376–1386) usingGeneral Method A

(yy)3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ7.61–7.54 (d, 1H), 5.15 (bs, 2H), 3.51–3.40(m, 5H), 2.39 (s, 3H), 2.01–1.95 (m, 4H), 1.21–1.11 (m, 2H), 0.67–0.62(m, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and pyrrolidine using General Method A.

(zz)3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ 7.49–7.42 (d, 1H), 5.13 (bs, 2H), 3.66–3.54(m, 4H), 3.50 (s, 3H), 3.42–3.31 (m, 1H), 2.02–1.92 (m, 4H), 1.17–1.07(m, 2H), 0.69–0.61 (m, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and pyrrolidine using General Method A.

(aaa)3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxyethyl-1-methyl)-pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ 7.59 (d, 1H), 5.15 (s, 2H), 3.68–3.53 (m,2H), 3.44–3.31 (m, 3H), 2.42 (s, 3H), 2.00–1.82 (m, 2H), 1.58 (s, 1H),1.28 (s, 6H), 1.20–1.10 (m, 2H), 1.00–0.80 (m, 1H), 0.66–0.60 (m, 2H))from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 1-methyl-1-pyrrolidin-3-yl-ethanol (Example A5n) usingGeneral Method A.

(bbb)3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione(¹H NMR (200 MHz, CDCl₃): δ 7.50 (d, 1H), 5.14 (s, 2H), 3.86–3.70 (m,2H), 3.49 (s, 3H), 3.60–3.30 (m, 3H), 2.40–2.22 (m, 1H), 2.00–1.80 (m,2H), 1.30 (s, 6H), 1.09–0.85 (m, 2H), 0.75–0.57 (m, 2H)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and 1-methyl-1-pyrrolidin-3-yl-ethanol (Example A5n) usingGeneral Method A.

(ccc)1-[(R)-1-(3-(S)-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[3-(1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione(MS ES: m/z 376 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-5-methyl-1H-quinazoline-2,4-dione(Example 24e) and methyl-((R)-((S)-1-pyrrolidin-3-yl)ethyl)amine usingGeneral Method A.

(ddd)1-[(R)-1-(3-(S)-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)-pyrrolidin-1-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(MS ES: m/z 406 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and ethyl-((R)-((S)-1-pyrrolidin-3-yl)ethyl)amine(Domagala J. M., Hagen S. E., Joannides T., Kiely J. S., Laborde E.,Schroeder M. C., Sesnie J. A., et al., J. Med. Chem., 1993;36[7]:871–882) using General Method A.

(eee)3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)-pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione(MS ES: m/z 390 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and ethyl-((R)-((S)-1-pyrrolidin-3-yl)ethyl)amine usingGeneral Method A.

(fff)3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(MS ES: m/z 390 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and 1-methyl-3-azabicyclo[3.2.0]hept-6-ylamine (Kim C. S.,Kim J. W., Lee J. M., Youn Y. S., Shin Y. J., Lee K. H., Kim J. H. WO94/15933) using General Method A.

(ggg)3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(MS ES: m/z 350 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and azetidin-3-ylmethylamine (Okada T., Ezumi K., YamakawaM., Sato H., Tsuji T., Tsushima T., Motokawa K., Komatsu Y., Chem.Pharm. Bull., 1993; 41:126–131) using General Method A.

(hhh)3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione(MS ES: m/z 378 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and piperidin-4-ylmethylamine using General Method A.

(iii)[(cis)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 482 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (cis-4-fluoropyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester [A5k)] using General Method A.

(jjj)[(trans)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-ylmethyl]carbamicacid tert-butyl ester (MS ES: m/z 482 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (trans-4-methylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester [A5l] using General Method A.

(kkk)[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-(1-amino-5-azaspiro[2.4]hept-5-yl)]carbamicacid tert-butyl ester (MS APCI: m/z 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 14d) and 1-amino-5-aza-spiro[2.4]hept-5-yl)]carbamic acidtert-butyl ester (Li Q., Chu D. T. W., Claiborne A., Cooper C. S., LeeC. M., Raye K., Berst K. B., et al., J. Med. Chem., 1996;39[16]:3070–3088) using General Method C.

(lll)[1-(3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl]carbamicacid tert-butyl ester (MS APCI: m/z 518 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 24d) and (3a-aminomethyloctahydro-isoindol-2-yl)carbamic acidtert-butyl ester (Ma Z., Chu D. T. W., Cooper C. S., Li Q., Fung A. K.L., Wang S., Shen L. L., et al., J. Med. Chem., 1999; 42(20):4202–4213)using General Method C.

(mmm)3-Amino-7-(3a-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione(MS APCI: m/z 502 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and 3a-aminomethyloctahydroisoindol-2-ylcarbamicacid-tert-butyl ester (Ma Z., Chu D. T. W., Cooper C. S., Li Q., Fung A.K. L., Wang S., Shen L. L., et al., J. Med. Chem., 1999; 42(20);4202–4213) using General Method C.

(nnn){(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamicacid tert-butyl ester (MS APCI: m/z 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione(Example 14d) and ((R)-(S)-1-pyrrolidin-3-yl)ethylcarbamic acidtert-butyl ester (J. Het. Chem., 1992; 29:1481) using General Method C.

(ooo){1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propyl}-carbamicacid tert-butyl ester (MS: m/e 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and (1-pyrrolidin-3-yl-propyl)-carbamic acid tert-butylester (Kimura Y., Atarashi S., Takahashi M., Hayakkawa I., Chem. Pharm.Bull., 1994; 42:1442) using General Method A.

(ppp){(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)pyrrolidin-3-yl]-ethyl}-methyl-carbamicacid dimethylethyl ester (MS: m/e 476 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and methyl-(R)-((S)-1-pyrrolidin-3-yl)ethylamine (PlummerJ. S., Emery L. A., Stier M. A., Suto M. J., Tetrahedron Lett., 1993;34(47):7529–7532) using General Method A.

(qqq){1-[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-aza-spiro[2.4]hept-7-yl]ethyl}carbamicacid tert-butyl ester (MS CI: m/e 488 (MH⁺)) from3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione(Example 24e) and [1-(5-aza-spiro[2.4]hept-7-yl)ethyl]carbamic acidtert-butyl ester (Example A5a) using General Method A.

EXAMPLE 29(7,8-Difluoro-3-methyl-2,3-dihydro-1,4-benzoxazin-4yl)-oxoacetaldehydeoxime

A solution of 8.27 g (50 mmol) of chloral hydrate in 125 mL of water istreated with 112.8 g (0.35 mmol) of sodium sulfate decahydrate. Themixture is stirred and treated with a solution of7,8-difluoro-3-methyl-3,4-dihydro-2H-benz[1,4]oxazine (Chem. Pharm.Bull., 1984; 32:4907) hydrochloride (prepared by dissolving 8.26 g (44.6mmol) of the free base in 50 mmol of concentrated hydrochloric acid in70 mL of 50% aqueous ethanol). The reaction is stirred and a solution of9.8 g (140 mmol) of hydroxylamine hydrochloride in 50 mL of water isadded. After heating at 75 to 80° C. for 3 hours, the reaction isstirred at room temperature overnight. The resulting precipitate isremoved by filtration, washed with water, and the wet filter cake isdissolved in dichloromethane. The organic solution is washed with water,dried (MgSO₄), decolorized with charcoal, filtered and concentrated invacuo to give 10.5 g of the title compound, mp 188–190° C.

EXAMPLE 30 Synthesis of6,7-Difluoro-3-methyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylene-1,2-dione

A solution of 45 mL of 98% sulfuric acid in 18 mL of water is heated to50° C. to 60° C. and treated portionwise over 30 minutes with 10.5 g (41mmol) of(7,8-difluoro-3-methyl-2,3-dihydro-1,4-benzoxazin-4-yl)oxoacetaldehydeoxime (Example 29). After the addition is complete, the reaction isheated to 80° C. for 15 minutes and poured onto 200 mL of ice and water.The mixture is stirred until the ice melts and the solid is removed byfiltration, washed with water and the wet filter cake is dissolved indichloromethane. The organic solution is washed with water (2×200 mL),dried (MgSO₄), filtered and concentrated in vacuo affording 7.1 g of thetitle compound, mp 169–171° C.

EXAMPLE 31 Synthesis of7,8-Difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

A suspension of 6.9 g (28.8 mmol) of6,7-difluoro-3-methyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylene-1,2-dione(Example 30) in 250 mL of 4.5% aqueous sodium hydroxide is treateddropwise with 16.4 mL of 30% hydrogen peroxide over 1 hour. The reactionis filtered to remove a trace of insoluble material and the filtrate isacidified to pH 4.5 with acetic acid. After cooling to 5° C., theprecipitate is removed by filtration, washed with water and dried invacuo to give 5.5 g of the title compound, mp 200–202° C.

EXAMPLE 32 Synthesis of Anthranilic Esters (a)7,8-Difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic

A solution of 2.1 g (9.1 mmol) of7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid(Example 31) in 50 mL of methanol is cooled to 0° C. and saturated withhydrogen chloride gas. The reaction is stirred at room temperature for18 hours, recooled to 0° C. and resaturated with hydrogen chloride gas.After stirring an additional 24 hours at room temperature, the solventis removed in vacuo and the residue is partitioned betweendichloromethane/5% aqueous sodium bicarbonate (200:100 mL). The organiclayer is separated, washed with 5% aqueous sodium bicarbonate, water,dried (MgSO4), filtered, and concentrated in vacuo affording 1.9 g ofthe title compound. ¹H NMR (400 MHz, CDCl₃): 7.27 (bs, 1H), 7.24 (m,1H), 4.26 (m, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.62 (m, 1H), 1.22 (d,3H).

(b) Synthesis of5,6-Difluoro-2-methyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acidmethyl ester

A solution of 8.0 g (33.7 mmol) of5,6-difluoro-2-methylquinoline-8-carboxylic acid methyl ester (Example33) in 100 mL of glacial acetic acid is treated with 2.15 g of platinumon carbon (0.8 g of active catalyst+62.8% water) and then shaken in ahydrogen atmosphere at temperatures of 24° C. to 29° C. and pressures of23.9 to 46.6 psi for 3 hours. The catalyst is removed by filtration andthe solvent is removed in vacuo at 50° C. The residue is triturated withwater (50 mL) and extracted with dichloromethane (2×200 mL). Thecombined organic layers are stirred with 5% sodium bicarbonate solution,washed with water, dried (MgSO₄), filtered and evaporated in vacuo. Theresidue is chromatographed over flash grade silica gel (230–400 mesh)eluting with dichloromethane to give 5.6 g of the title compound as alight yellow oil. ¹H NMR (400 MHz, CDCl₃): 7.66 (bs, 1H), 7.49 (m, 1H),3.82 (s, 3H), 3.46 (m, 1H), 2.88 (m, 1H), 2.67 (m, 1H), 1.97 (m, 1H),1.27 (d, 3H).

EXAMPLE 33 Synthesis of 5,6-Difluoro-2-methylquinoline-8-carboxylic acidmethyl ester

In a stainless steel reactor, a solution of 9.53 g (36.9 mmol) of8-bromo-5,6-difluoro-2-methylquinoline (Chem. Pharm. Bull., 1996;44:642), 6.8 g (67.6 mmol) of triethylamine, 0.67 g (3.0 mmol) ofpalladium (II) acetate, 1.28 g (3.1 mmol) of1,3-bis(diphenyl-phosphino)propane in 90 mL of dimethylformamide and 65mL of methanol is flushed with nitrogen gas and pressurized to 550 psiwith carbon monoxide. The reaction is rocked and heated to 75° C. for 24hours, cooled to room temperature and evaporated in vacuo. The residueis triturated with water (50 mL) and extracted with dichloromethane(2×200 mL). The combined organic layers are washed with water (2×50 mL),dried (MgSO₄), filtered and evaporated in vacuo. The residue ischromatographed over flash grade silica gel (230–400 mesh) eluting withdichloromethane (200 mL), then dichloromethane/ethyl acetate (90:10) togive 8.0 g of the title compound, mp 99–101° C.

EXAMPLE 34 Synthesis of2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinic acid ethyl ester

A solution of 8.7 g (34.8 mmol) of2-chloro-5-fluoro-6-methylsulfanylnicotinic acid ethyl ester (J. Med.Chem., 1993; 36:2676) and 5.7 g (100 mmol) of cyclopropylamine in 100 mLof acetonitrile is heated at reflux for 18 hours. After TLC showed thepresence of unreacted starting material, 4.12 g (72 mmol) ofcyclopropylamine is added and the reaction mixture is refluxed for 48hours. The solvent is removed in vacuo and the residue is partitionedbetween dichloromethane (250 mL) and water (100 mL). The organic layeris washed with water, dried (MgSO₄), filtered, and concentrated invacuo. The residue is chromatographed over flash grade silica gel(230–400 mesh) eluting with dichloromethane to give 6.5 g of the titlecompound, mp 67–69° C.

EXAMPLE 35 Synthesis of1-Cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-7-thiosulfonicacid)

A solution of 0.65 g (2.4 mmol) of1-cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione(Example 23e) in 20 mL of formic acid is treated with 1.83 g (19.5 mmol)of urea-hydrogen peroxide and the reaction mixture is stirred at roomtemperature overnight. The resulting precipitate is removed byfiltration, washed with water, ethyl acetate and dried in vacuo to give0.63 g of the title compound, mp 300–302° C.

EXAMPLE 36 Synthesis of{8-Chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylamino-methyl)pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester

A solution of(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamicacid tert-butyl ester (Example 14, 0.37 g, 0.97 mmol) in acetonitrile(20 mL) is added pyrrolidin-3-yl-methylamine (0.115 g, 1.16 mmol) andtriethylamine (2.7 mL, 19.3 mmol). After refluxing for 20 hours, thereaction mixture is cooled to room temperature and diluted with ethylacetate. The organic layer is washed with saturated sodium bicarbonate,water, and brine. The organic layer is dried over MgSO₄, filtered, andthe filtrate concentrated. The resulting residue is redissolved inmethylene chloride (10 mL) at 0° C. and while stirring, triethylamine(0.33 mL, 2.34 mmol) and methanesulfonyl chloride (0.072 mL, 0.94 mmol)is added. After 2 hours, the reaction mixture is diluted with ethylacetate and washed with saturated sodium bicarbonate, water, and brine.The organic layer is dried over MgSO₄, filtered, and the filtrateconcentrated and the product is purified via flash column chromatography(1:1 EtOAc/hexanes) to afford{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamicacid tert-butyl ester (0.043 g). MS CI: m/e 446 ((MH⁺)-Boc).

Amine Side Chain Synthesis EXAMPLE A1 (a)5-Benzyl-5-azaspiro[2,4]heptan-1-carboxylic acid ethyl ester

A solution of cyclopropylidene acetic acid ethyl ester (192 g, 1520 mmol[Salaun J., Bennani F., Compain J. C., Fadel A., Ollivier J. J,. OrgChem., 1980; 45(21):4129–3415]) andN-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (572 g, 2410 mmol[Gerlach K., Hoffmann H. M. R., Wartchow R. J., Chem. Soc., PerkinTrans. 11, 1998(22):3867–3872]) in dichloromethane (5.5 L) was treatedwith a solution of 1.0N trifluoroacetic acid in dichloromethane (80 mL)and the reaction is stirred at ambient temperature for 30 minutes. Thesolvent is then evaporated at reduced pressure and the product purifiedby Kugelrohr distillation (277 g). MS CI: m/z 260 (MH⁺).

EXAMPLE A2 (a) Synthesis of1-(5-Benzyl-5-azaspiro[2.4]hept-7-yl)ethanone

A solution (−78° C.) of 5-benzyl-5-azaspiro[2.4]heptane-7-carboxylicacid ethyl ester (Example A1a, 8.15 g, 31.4 mmol) in diethyl ether (200mL) under a nitrogen atmosphere is treated with methyllithium (1.4 M indiethyl ether, 22.4 mL, 31.4 mmol) over a period of 10 minutes. After 1hour, reaction mixture is warmed to −10° C. and quenched with saturatedaqueous ammonium chloride. The mixture is poured into a separatoryfunnel and the organic layer is washed with saturated aqueous ammoniumchloride, water, and brine. The organic layer is then dried with MgSO₄,filtered, and the filtrate concentrated. The resulting residue ispurified via flash column chromatography (1% triethylamine/7%isopropanol/92% CH₂Cl₂) to afford the title compound (3.93 g). MS CI:m/z 230 (MH⁺).

EXAMPLE A3 (a) Synthesis of1-(5-Benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime

1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone (Example A2a, 3.93 g, 17.1mmol) and hydroxylamine hydrochloride (1.78 g, 25.7 mmol) are stirred inpyridine (10 mL) at 90° C. After 20 hours, the reaction mixture isdiluted with ethyl acetate and the organic layer is washed withsaturated NaHCO₃, water, and brine. The organic layer is dried withMgSO₄, filtered, and the filtrate concentrated to afford1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime as an oil (3.07 g).MSCI: m/z 245 (MH⁺).

General Method A

A solution of substrate, hydroxylamine hydrochloride (1.2 eq.), sodiumacetate (0.9 eq.) in ethanol is stirred at room temperature for 2 hours.The solvent is removed in vacuo and the residue is partitioned betweenethyl acetate and saturated sodium chloride solution. The aqueous isre-extracted with ethyl acetate and the combined extracts are dried overNa₂SO₄, filtered and concentrated under vacuum to afford the titlecompound.

The compounds below were prepared according to General Method A.

(b) 1-(1-Benzylpiperidin-3-yl)ethanone oxime (¹H NMR (200 MHz, CDCl₃): δ7.48–7.28 (m, 5H), 3.92–3.68 (m, 2H), 3.28–3.0 (m, 4H), 2.88–2.62 (m,2H), 2.38–1.72 (m, 3H), 1.3–1.18 (m, 3H)) from1-(1-benzylpiperidin-3-yl)ethanone (Example A23).

(c) 1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone oxime (¹H NMR (200MHz, CDCl₃): δ 7.68–7.30 (m, 5H), 6.60–5.80 (bs, 1H), 3.80–2.38 (m, 6H),1.90 (s, 3H), 1.38–0.96 (m, 7H)) from1-(1-benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone (Example A18b).

(d) 1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethanone oxime (¹H NMR (200 MHz,CDCl₃): δ 7.41–7.15 (m, 51H), 3.78–3.44 (m, 3H), 2.98–2.80 (m, 1H),2.75–2.39 (m, 3H), 2.35–2.08 (m, 2H), 1.90 (m, 3H), 1.18–0.95 (m, 3H))from 1-(1-benzyl-4-methylpyrrolidin-3-yl)ethanone (Example A23b).

EXAMPLE A4 (a) Synthesis of1-(5-Benzyl-5-azaspiro[2.4]hept-7-yl)-ethyl]carbamic acid tert-butylester

To a solution of 1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethanone oxime(Example A3,a, 2.90 g, 11.9 mmol) in methanol (100 mL) is addedRaney-Nickel (2 g). Hydrogen is introduced to the reaction mixture athigh pressure (48 psi) for 20 hours and the reaction mixture is filteredthrough celite, washed with methanol, and the combined filtratesconcentrated in vacuo. The resulting residue is redissolved indichloromethane (25 mL) and treated with di-tert-butyl dicarbonate (3.24g, 14.9 mmol). After 1 hour, the mixture is concentrated and the productpurified via flash column chromatography (1% triethylamine/7%isopropanol/92% dichloromethane) to afford[1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)-ethyl]carbamic acid tert-butylester (1.47 g). MS CI: m/z 331 (MH⁺).

General Method A

Di-tert-butyl dicarbonate (0.69 g, 0.3 mmol) is added to a solution ofamine in methanol (4 mL) at 0° C. After stirring at room temperature for2 hours, the mixture is concentrated and the residue is purified bychromatography (SiO₂, ethyl acetate/hexanes) to afford the titlecarbamic esters.

General Method B

An ice-cold solution of substrate in 2:1 methanol and water is treatedwith di-tert-butyl dicarbonate (1.25 eq.). The resulting solution isstirred at room temperature for 18 hours and extracted withdichloromethane. The organic extracts are washed with brine, dried overNa₂SO₄, filtered and concentrated under vacuum. The residue is purifiedby flash column chromatography (ethyl acetate/hexanes) to afford thetitle compounds.

General Method C

To a solution of substrate in dichloromethane is added di-tert-butyldicarbonate (2 eq.) and triethylamine (2 eq.). The resulting mixture isstirred at room temperature for 18 hours and diluted with water. Theorganic extract is washed with water, brine, dried over Na₂SO₄, filteredand concentrated in vacuo. The residue is then purified by columnchromatography to afford the title compound.

Examples A4b–A4m are prepared according to General Methods A, B, and C.

(b)3-(1-tert-Butoxycarbonylaminoethyl)-3-methoxypyrrolidine-1-carboxylicacid benzyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.37–7.29 (m, 5H), 5.13(s, 2H), 4.70 (bs, 1H), 3.91–3.22 (m, 8H), 2.03–1.75 (m, 2H), 1.43 (s,9H), 1.16–1.11 (m, 3H)) from3-(1-aminoethyl)-3-methoxypyrrolidine-1-carboxylic acid benzyl ester(Example A13a) using General Method A.

(c) 3-(1-tert-Butoxycarbonylaminoethyl)-3-fluoropyrrolidine-1-carboxylicacid benzyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.35 (s, 5H), 5.13 (s,2H), 4.79 (d, 1H), 3.97–3.26 (m, 5H), 2.17–1.75 (m, 2H), 1.44 (s, 9H),1.24 (d, 3H)) from 3-(1-aminoethyl)-3-fluoropyrrolidine-1-carboxylicacid benzyl ester (Example A13b) using General Method A.

(d) (1-Benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.35–7.17 (m, 5H), 5.78(bs, 1H), 3.56 (s, 2H), 3.32 (s, 3H), 3.27 (s, 2H), 3.21–3.12 (m, 2H),2.71–2.62 (m, 1H), 2.54–2.30 (m, 3H), 1.78–1.54 (m, 2H), 1.46 (s, 9H))from (1-benzyl-3-methoxymethylpyrrolidin-3-yl)methylamine (Example A13c)using General Method B.

(e) [1-(1-Benzylpiperidin-3-yl)ethyl]carbamic acid tert-butyl ester (¹HNMR (200 MHz, CDCl₃): δ 7.3 (s, 5H), 4.46–4.30 (m, 1H), 3.62–3.42 (m,4H), 2.94–2.62 (m, 3H), 2.0–1.0 (m, 8H), 1.44 (s, 9H)) from1-(1-benzylpiperidin-3-yl)ethylamine (Example A13d) using General MethodC.

(f) [1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic acidtert-butyl ester (¹H NMR (200 MHz, CDCl₃): Isomer-1: δ 7.36–7.22 (m,5H), 3.82–3.38 (m, 2H), 2.98–1.78 (m, 5H), 1.52–1.0 (m, 19H); Isomer-2:δ 7.35–7.25 (m, 5H), 4.35–4.18 (m, 1H), 3.70–3.45 (m, 2H), 2.90–1.54 (m,6H), 1.43 (s, 9H), 1.18–0.92 (m, 9H)) from1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethylamine (Example A13e) usingGeneral Method C.

(g) [1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethyl]carbamic acid tert-butylester (¹H NMR (200 MHz, CDCl₃): δ 7.38–7.13 (m, 5H), 3.71–3.32 (m, 4H),3.08–1.53 (m, 6H), 1.52–1.31 (m, 9H), 1.14–0.94 (m, 6H). MS ES: m/z 319(MH⁺)) from 1-(1-benzyl-4-methylpyrrolidin-3-yl)ethylamine (ExampleA13f) using General Method C.

(h) (5-Benzyl-5-azaspiro[2,4]hept-7-ylmethyl)carbamic acid tert-butylester (MS ES: m/z 317 (MH⁺)) from1-(5-benzyl-5-azaspiro[2,4]hept-7-yl)methylamine (Example A13g) usingGeneral Method C.

(i) (1-Benzyl-3-hydroxypyrrolidin-3-ylmethyl)carbamic acid tert-butylester (MS ES: m/z 307 (MH⁺)) from 3-aminomethyl-1-benzylpyrrolidin-3-ol(Grohe K., Schriewer M., Haller I., Metzger K., Endermann R., Zeiler H.,EP 0326916) using General, Method C.

(j) [3-(1 Phenylethyl)-3-azabicyclo[3.1.0]hex-1-ylmethylcarbamic acidtert-butyl ester (MS ES: m/z 317 (MH⁺)) from1-[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hex-1-yl]methylamine (ExampleA13h) using General Method C.

(k) (1,3-Dibenzylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester(MS EI+: m/z 381 (MH⁺)) using 1-(1,3-dibenzylpyrrolidin-3-yl)methylamine(Example A13i) using General Method C.

(l) (1-Benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid tert-butylester (¹H NMR (200 MHz, CDCl₃): δ 7.30 (s, 5H), 5.04 (m, 1H), 5.04 (m,1H), 4.77 (m, 1H), 3.63 (s, 2H), 3.20 (t, 2H), 2.86–3.00 (m, 2H), 2.76(d, 1H), 2.20–2.60 (m, 2H), 1.45 (s, 9H)) from(1-benzyl-4-fluoropyrrolidin-3yl)methylamine (Bouzard D., Di Cesare P.,Essiz M., Jacquet J. P., Kiechel J. R., Remuzon P., Weber A., et al., J.Med. Chem., 1990; 33:1344–1352) using General Method C.

(m) cis-(1-Benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid tert-butylester (¹H NMR (200 MHz, CDCl₃): δ 7.30 (s, 5H), 5.04 (m, 1H), 4.77 (m,1H), 3.63 (s, 2H), 3.20 (t, 2H), 3.00–2.86 (m, 2H), 2.76 (d, 1H),2.60–2.20 (m, 2H), 1.45 (s, 9H)) fromcis-(1-benzyl-4-fluoro-pyrrolidin-3-yl)methylamine (Matsumoto J., NakanoJ., Chiba K., Minamida A., Nishimura Y., Jpn. Kokai Tokkyo Koho, 1987;11 pp., JP 62072660, A2 19870403) using General Method C.

(n) trans-(1-Benzyl-4-fluoropyrrolidin-3-ylmethylcarbamic acidtert-butyl ester (¹H NMR (200 MHz, CDCl₃): δ 7.30 (s, 5H), 5.25 (m, 1H),4.77 (m, 1H), 3.85 (s, 2H), 3.55 (t, 2H), 3.40–2.40 (m, 5H), 1.47 (s,9H) from trans-(1-benzyl-4-fluoropyrrolidin-3-yl)methylamine (MatsumotoJ., Nakano J., Chiba K., Minamida A., Nishimura Y., Jpn. Kokai TokkyoKoho, 1987; 11 pp., JP 62072660, A2 19870403) using General Method C.

(o) (1-Benzyl-3-phenylpyrrolidine-3-ylmethyl)carbamic acid tert-butylester (MS ES: m/z 367 (MH⁺)) from(1-benzyl-3-phenylpyrrolidine-3-yl)methylamine ester (Hagen S., DomagalaJ. M., Heifetz C. L., Sanchez J. P., Solomon M., J. Med. Chem., 1990;33:849–854) using General Method C.

EXAMPLE A5 (a) Synthesis of [1-(5-Azaspiro[2.4]hept-7-yl)ethyl]carbamicacid tert-butyl ester

A solution of [1-(5-benzyl-5-azaspiro[2.4]hept-7-yl)ethyl]carbamic acidtert-butyl ester (Example A4a, 1.47 g) in methanol (30 mL) in a Parrshaker is treated with 10% palladium on carbon (0.5 g) and hydrogenintroduced (50 psi) for 24 hours. The reaction mixture is filteredthrough celite, washed with methanol, and the combined filtrateconcentrated in vacuo to afford the title compound. MS CI: m/z 241(MH⁺).

General Method A

To a solution of substrate in methanol is added ammonium formate (5 eq.)and 10% palladium on charcoal (0.75 wt. vol. eq.). After 2 hours atreflux, the reaction mixture is cooled, diluted with dichloromethane andfiltered. The filtrate is concentrated to afford the title compound.

Examples A5b–A5o are prepared using General Method A.

(b) [1-(3-Methoxypyrrolidin-3-yl)ethyl]carbamic acid tert-butyl ester(¹H NMR (200 MHz, CDCl₃): δ 5.30 (bs, 1H), 5.03 (dd, 1H), 3.92 (bs, 1H),3.28–2.82 (m, 7H), 1.97–1.72 (m, 2H), 1.44 (s, 9H), 1.19–1.14 (m, 3H))from3-(1-tert-butoxycarbonylaminoethyl)-3-methoxypyrrolidine-1-carboxylicacid benzyl ester (Example A4b) using General Method A.

(c) [1-(3-Fluoropyrrolidin-3-yl)ethyl]carbamic acid tert-butyl ester (¹HNMR (200 MHz, CDCl₃): δ 4.89 (d, 1H), 3.95–3.61 (m, 1H), 3.21–2.70 (m,4H), 2.11–1.53 (m, 1H), 1.44 (s, 9H), 1.26 (d, 3H)) from3-(1-tert-butoxycarbonylaminoethyl)-3-fluoropyrrolidine-1-carboxylicacid benzyl ester (Example A4c) using General Method A.

(d) (3-Methoxymethylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester(¹H NMR (200 MHz, CDCl₃): δ 5.25 (bs, 1H), 3.35 (s, 3H), 3.30 (s, 2H),3.27–3.15 (m, 2H), 3.09–2.94 (m, 2H), 2.78 (s, 2H), 1.68–1.56 (m, 2H),1.45 (s, 9H). (MS ES: m/z 245 (MH⁺)) from(1-benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)carbamic acid tert-butylester (Example A4d) using General Method A.

(e) (1-Piperidin-3-ylethyl)carbamic acid tert-butyl ester (¹H NMR (200MHz, CDCl₃): δ 4.52–4.32 (m, 1H), 3.68–3.18 (m, 4H), 2.74–2.42 (m, 1H),2.02–1.2 (m, 5H), 1.44 (s, 9H), 1.30–1.04 (m, 3H)) from[1-(1-benzylpiperidin-3-yl)ethyl]carbamic acid tert-butyl ester (ExampleA4e) using General Method A.

(f) [1-(4,4-Dimethylpyrrolidin-3-yl)ethyl]carbamic acid tert-butyl ester(¹H NMR (200 MHz, CDCl₃): 6.28–5.85 (bs, 1H), 4.75 (d, 1H), 3.92–1.80(m, 6H), 1.43 (s, 9H), 1.30–1.0 (9H)) from[1-(1-benzyl-4,4-dimethylpyrrolidin-3-yl)ethyl]carbamic acid tert-butylester (Example A4f).

(g) [1-(4-Methylpyrrolidin-3-yl)ethyl]carbamic acid tert-butyl ester (¹HNMR (200 MHz, CDCl₃): δ 4.88–4.40 (m, 1H), 4.02–3.38 (m, 4H), 3.25–2.75(m, 2H), 2.46–1.88 (m, 2H), 1.44 (s, 9H), 1.31–1.04 (m, 6H)) from[1-(1-benzyl-4-methylpyrrolidin-3-yl)ethyl]carbamic acid tert-butylester (Example A4g).

(h) (5-Azaspiro[2,4]hept-7-ylmethyl)carbamic acid tert-butyl ester (MSES: m/z 227 (MH⁺)) from(5-benzyl-5-azaspiro[2,4]hept-7-ylmethyl)carbamic acid tert-butyl ester(Example A4h).

(i) (3-Hydroxypyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester (MSES: m/z 217 (MH⁺)) using(1-benzyl-3-hydroxypyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester(Example A4i).

(j) (3-Azabicyclo[3.1.0]hex-1-ylmethyl)carbamic acid tert-butyl ester(MS ES: m/z 213 (MH⁺)) using[3-(1-phenylethyl)-3-azabicyclo[3.1.0]hex-1-ylmethylcarbamic acidtert-butyl ester (Example A4j).

(k) cis-(4-Fluoropyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester(¹H NMR (200 MHz, CDCl₃): δ 5.60–5.00 (m, 4H), 3.60–3.10 (m, 4H), 3.00(t, 1H), 2.75–2.30 (m, 1H), 1.44 (s, 9H)) usingcis-(1-benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid tert-butylester (Example A4l).

(l) trans-(4-Fluoropyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester(¹H NMR (200 MHz, CDCl₃): δ 6.60–5.70 (m, 2H), 5.25 (bs, 0.5H), 4.98(bs, 0.5H), 3.70–2.90 (m, 5H) 2.90–2.50 (m, 1H), 1.44 (s, 9H)) usingtrans-(1-benzyl-4-fluoropyrrolidin-3-ylmethyl)carbamic acid tert-butylester (Example A4m).

(m) 3-Hydroxy-4-hydroxymethylpyrrolidine (¹H NMR (200 MHz, DMSO-d₆): δ5.50–4.30 (bs, 3H), 4.30–1.50 (m, 8H)) using1-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (Jaeger E., Biel J. H., J.Org. Chem., 1965; 30:740–744).

(n) 1-Methyl-1-pyrrolidin-3-yl-ethanol (MS ES: m/z 130 (MH⁺)) from2-(1-benzylpyrrolidin-3-yl)propan-2-ol (Example A25).

(o) (3-benzylpyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester (mp183–185° C.) from (1,3-dibenzylpyrrolidin-3-ylmethyl)carbamic acidtert-butyl ester (Example A4K).

(p) A5p (3-Phenylpyrrolidine-3-ylmethyl)carbamic acid tert-butyl ester(MS APCI: m/z 277 (MH⁺)) from(1-benzyl-3-phenylpyrrolidine-3-ylmethyl)carbamic acid tert-butyl ester(Example A4o).

EXAMPLE A6 Synthesis of 1-Benzylpyrrolidin-3-one oxime

To a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.71 mmol) in pyridine(5 mL) is added hydroxylamine hydrochloride (0.59 g, 8.57 mmol). Afterstirring at 90° C. for 5 hours, the reaction mixture is diluted withethyl acetate and washed with saturated sodium bicarbonate, water, andbrine. The organic layer is dried over MgSO₄, filtered, and filtrateconcentrated to afford 1-benzylpyrrolidin-3-one oxime (1.11 g) as anoil. MS CI: m/z 191 (MH⁺).

EXAMPLE A7 Synthesis of Pyrrolidin-3-one oxine

In a Parr shaker, 1-benzylpyrrolidin-3-one oxime (1.5 g) in methanol (20mL) is treated with 20% palladium on carbon (0.5 g) under Hydrogenpressure (50 psi) for 24 hours. The mixture is then filtered throughCelite, washed with methanol, and the combined filtrate concentrated invacuo to afford the title compound as an oil (1.2 g). MS CI: m/e 101(M⁺+1).

EXAMPLE A8 Synthesis of 3-Ethylidenepyrrolidine-1-carboxylic acid benzylester

Under an inert atmosphere, sodium-hydride (0.160 g, 7 mmol) andethyltriphenylphosphonium bromide (2 g, 5.4 mmol) are mixed in drydimethyl sulfoxide (10 mL) and stirred for 40 minutes.3-Oxopyrrolidine-1-carboxylic acid benzyl ester (1.18 g, 5.4 mmol (J.Med. Chem., 1992; 35:1392)) in dry dimethyl sulfoxide (5 mL) is added tothe reaction and the mixture is stirred at 70° C. for 3 hours. Thereaction is cooled, diluted with cold water and extracted with ethylacetate. The organic phase is washed with brine, dried over Na₂SO₄ andevaporated. The residue is purified by column chromatography (65:35hexanes/ethyl acetate) to afford the title compound (0.650 g) as aviscous oil. ¹H NMR (200 MHz, CDCl₃): δ 7.37–7.28 (m, 5H), 5.40–5.32 (m,1H), 5.15 (s, 2H), 3.97 (bs, 2H), 3.60–3.44 (m, 2H), 2.49 (bs, 2H),1.65–1.60 (m, 3H).

EXAMPLE A9 Synthesis of2-Methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic acid benzyl ester

A solution of 3-ethylidenepyrrolidine-1-carboxylic acid benzyl ester(Example A8, 0.65 g, 2.8 mmol) and 3-chloroperoxybenzoic acid (0.86 g, 5mmol) in dichloromethane (15 mL) is stirred at room temperature for 3hours. The excess peracid is decomposed by the addition of 10% sodiumsulfite. The organic layer is washed with 5% sodium bicarbonatesolution, dried over Na₂SO₄ and evaporated. The residue is purified bycolumn chromatography (1:1 hexanes/ethyl acetate) to afford the titlecompound (0.310 g). ¹H NMR (200 MHz, CDCl₃): δ 7.36–7.26 (m, 5H), 5.14(s, 2H), 3.73–3.55 (m, 3H), 3.34 (d. 1H), 3.20–3.13 (m, 1H), 2.26–2.11(m, 1H), 1.90–1.62 (m, 1H), 1.33 (d, 3H).

EXAMPLE A10 Synthesis of3-(1-Aminoethyl)-3-hydroxypyrrolidine-1-carboxylic acid benzyl ester

A solution of 2-methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic acidbenzyl ester (Example A9, 0.31 g, 1.25 mmol) in methanol (10 mL) andammonium hydroxide (7 mL) is heated in a sealed tube at 100° C. for 16hours. After cooling, the reaction mixture is dissolved ethyl acetate,washed with water, dried over Na₂SO₄ and evaporated to afford the titlecompound (0.340 g). ¹H NMR (200 MHz, CDCl₃): δ 7.33–7.26 (m, 5H), 5.28(bs, 2H), 5.07 (s, 2H), 3.56–3.16 (m, 5H), 2.03–1.76 (m, 2H), 1.15 (d,3H).

EXAMPLE A11 Synthesis of3-Hydroxy-3-{1-[(2-hydroxybenzylidene)amino]ethyl}pyrrolidine-1-carboxylicacid benzyl ester

A solution of 3-(1-aminoethyl)-3-hydroxypyrrolidine-1-carboxylic acidbenzyl ester (Example A10, 0.34 g, 0.93 mmol) and salicylaldehyde (0.147g, 1.2 mmol) in dry ethanol (5 mL) is refluxed for 3 hours. Afterevaporation of the solvent, the residue is purified by columnchromatography (30:70:0.01 ethyl acetate/hexanes/ammonium hydroxide) toafford the title compound (0.12 g). ¹H NMR (200 MHz, CDCl₃): δ 8.39 (s,1H), 7.41–7.25 (m, 7H), 6.97–6.85 (m, 2H), 5.09 (s, 2H), 3.65–3.34 (m,5H), 2.01–1.87 (m, 2H), 1.37–1.32 (m, 3H).

EXAMPLE A12 Synthesis of3-Methoxy-3-{1-[(2-methoxybenzylidene)amino]ethyl}pyrrolidine-1-carboxylicacid benzyl ester

To a stirred solution of3-hydroxy-3-{1-[(2-hydroxybenzylidene)amino]-ethyl}pyrrolidine-1-carboxylicacid benzyl ester (Example A11, 0.120 g, 0.33 mmol) in tetrahydrofuran(5 mL) at 0° C. is added 0.024 g (1 mmol) of sodium hydride. The mixtureis stirred at room temperature for 2 hours and methyl iodide (3 mL) isadded and stirring was continued overnight. After evaporation, ethylacetate and water are added to the residue. The organic layer isseparated, dried over Na₂SO₄ and concentrated to afford the titlecompound (0.125 g). ¹H NMR (200 MHz, CDCl₃): δ 8.70 (s, 1H), 7.95 (d,1H), 7.41–7.32 (m, 6H), 7.01–6.88 (m, 2H), 5.09 (s, 2H), 3.86 (s, 3H),3.72–3.22 (m, 8H), 2.33–1.73 (m, 2H), 1.27–1.24 (m, 3H).

EXAMPLE A13 (a) Synthesis of3-(1-Aminoethyl)-3-methoxypyrrolidine-1-carboxylic acid benzyl ester

A solution of3-methoxy-3-{1-[(2-methoxybenzylidene)amino]ethyl-pyrrolidine-1-carboxylicacid benzyl ester (Example A12, 0.120 g, 0.3 mmol) in 3 M hydrogenchloride in methanol (1 mL) is heated at 40° C. overnight. The reactionis basified, extracted with ethyl acetate and the organic layer is driedover Na₂SO₄. After concentration, the residue is purified by columnchromatography (20:80 methanol/dichloromethane) to afford the titlecompound (0.060 g). ¹H NMR (200 MHz, CDCl₃): δ 7.38–7.29 (m, 5H), 5.12(s, 2H), 3.64–3.19 (m, 8H), 2.47 (bs, 2H), 2.07–1.80 (m, 2M), 1.16–1.10(m, 3H).

(b) 3-(1-Aminoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester

A solution of 3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylic acidbenzyl ester (Example A16, 0.16 g, 0.5 mmol) in methanol (10 mL) istreated with Raney nickel (100 mg, wet weight) and shaken in a hydrogenatmosphere at room temperature and at 55 psi for 17 hours. The catalystis removed by filtration through Celite, and the solvent is removed invacuo to afford the title compound (0.12 g). ¹H NMR (200 MHz, CDCl₃): δ7.30 (s, 5H), 5.12 (s, 2H), 3.84–3.22 (m, 5H), 2.23–1.79 (m, 4H), 1.20(d, 3H).

(c) 1-(1-Benzyl-3-methoxymethylpyrrolidin-3-yl)methylamine

Hydrazine hydrate (85% solution in water, 0.372 g, 6.32 mmol) is addedto a solution of2-(1-benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)isoindole-1,3-dione(Example A20, 1.581 g, 4.34 mmol) in ethanol (50 mL). The resultingmixture is refluxed for 4.5 hours, cooled and acidified withconcentrated hydrochloric acid. The precipitate is removed by filtrationand the filtrate is concentrated in vacuo. The residue is dissolved inethanol/water (2:1) and the insoluble material is removed by filtration.The filtrate is basified to pH 10 with 1N sodium hydroxide solution andextracted with dichloromethane. The combined organic extracts are driedover Na₂SO₄, filtered and concentrated under vacuum to afford the titlecompound (0.910 g). ¹H NMR (200 MHz, CDCl₃): δ 7.41–7.15 (m, 5H), 3.57(s, 2H), 3.33 (s, 3H), 3.30 (s, 2H), 2.71 (s, 2H), 2.64–2.51 (m, 2H),2.42–2.24 (m, 2H), 1.68–1.52 (m, 2H), 1.38–1.10 (m, 2H).

General Method A

Lithium aluminium hydride (2 eq.) is slowly added to a solution ofoxime, nitrile, or amide derivative in dry tetrahydrofuran. After theaddition is complete, the mixture is refluxed for 2 to 6 hours, cooledin an ice bath and quenched with saturated sodium sulfate solution. Thesolid is removed by filtration and the filtrate is concentrated in vacuoto afford the title compound.

Examples A13d–i are prepared according to General Method A.

(d) 1-(1-Benzylpiperidin-3-yl)ethylamine (¹H NMR (200 MHz, DMSO-d₆): δ7.38–7.18 (m, 5H), 3.52–3.22 (m, 2H), 2.82–2.58 (m, 3H), 1.92–0.75 (m,10H)) from 1-(1-benzylpiperidin-3-yl)ethanone oxime (Example A3b).

(e) 1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethylamine (¹H NMR (200 MHz,CDCl₃): δ 7.36–7.22 (m, 5H), 3.66–3.42 (m, 2H), 2.94–2.10 (m, 5H),1.32–0.88 (m, 10H)) from1-(1-benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone oxime (Example A3c).

(f) 1-(1-Benzyl-4-methylpyrrolidin-3-yl)ethylamine (¹H NMR (200 MHz,CDCl₃): δ 7.38–7.11 (m, 5H), 3.63–3.12 (m, 2H), 2.78–2.27 (m, 5H),2.23–1.18 (m, 4H), 1.10–0.78 (m, 6H)) from1-(1-benzyl-4-methylpyrrolidin-3-yl)ethanone oxime (Example A3d).

(g) 1-(5-Benzyl-5-azaspiro[2,4]hept-7-yl)methylamine (¹H NMR (CDCl₃): δ7.36–7.21 (m, 5H), 3.68–3.53 (m, 2H), 3.1 (dd, 1H), 2.61–2.38 (m, 5H),2.1–1.92 (m, 1H), 1.29 (bs, 2H), 0.72–0.32 (m, 4H)) from5-benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid amide (Example A24).

(h) 1-[3-(1-Phenylethyl)-3-azabicyclo[3.1.0]hex-1-yl]methylamine (MS ES:m/z 217 (MH⁺)) from3-(1-phenylethyl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile (Takemura M.,Kimura Y., Kawakami K., EP 0807630).

(i) 1,3-Dibenzyl-3-pyrrolidinemethanamine (MS El: m/z 281 (MH⁺)) from1,3-dibenzyl-3-pyrrolidine carboxamide (Example A29).

EXAMPLE A14 Synthesis of3-Fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester

A solution of 0.247 g, (1 mmol) of2-methyl-1-oxa-5-azaspiro[2,4]-heptane-5-carboxylic acid benzyl ester(Example A9) in dichloromethane (3 mL) is added to a polypropylene flaskcontaining 0.5 mL of hydrogen fluoride-pyridine at −40° C. The reactionis allowed to come to room temperature and stirring is continued for 3hours. The reaction mixture is poured into an aqueous ice-cold ammoniumhydroxide solution (30 mL) and extracted with dichloromethane. Theorganic layer is dried, filtered and concentrated to afford the titlecompound (0.267 g). ¹H NMR (200 MHz, CDCl₃): δ 7.35 (s, 5H), 5.13 (s,2H), 3.96–3.34 (m, 5H), 2.20–1.98 (m, 3H), 1.33–1.26 (m, 3H).

EXAMPLE A15 Synthesis of3-Fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acidbenzyl ester

To a −10° C. solution of3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester(Example A14, 0.267 g, 1.00 mmol), triethylamine (0.4 g, 4 mmol) anddichloromethane (10 mL) is added methanesulfonyl chloride (0.229 g, 2.00mmol). The mixture is stirred at room temperature for 2 hours andconcentrated in vacuo. The residue is partitioned between ethyl acetateand water. The organic layer is dried over Na₂SO₄ and concentrated toafford the title compound (0.330 g). ¹H NMR (200 MHz, CDCl₃): δ 7.36 (s,5H), 5.14 (s, 2H), 4.99–4.81 (m, 1H), 3.76–3.37 (m, 4H), 3.06 (s, 3H),2.25–1.96 (m, 2H), 1.52–1.47 (m, 3H).

EXAMPLE A16 Synthesis of3-(1-Azidoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester

To a solution of3-fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acidbenzyl ester (Example A15, 0.25 g, 0.72 mmol) in N,N-dimethylformamide(5 mL) is added sodium azide (0.13 g, 2 mmol). The reaction mixture isheated at 120° C. overnight. The mixture is diluted with water andextracted with ethyl acetate. The extracts are washed with brine, driedover Na₂SO₄ and concentrated to afford the title compound (0.160 g). ¹HNMR (200 MHz, CDCl₃): δ 7.28 (s, 5H), 5.08 (s, 2H), 3.80–3.25 (m, 5H),2.13–1.75 (m, 2H), 1.40 (d, 3H).

Example A17

Synthesis of 2-Methoxymethylacrylic acid ethyl ester

A solution of ethyl α-(bromomethyl)acrylate (0.99 g, 5.1 mmol [VillierasJ., Rambaud M., Synthesis, 1982:924–926]) in methanol (10 mL) is addedto an ice-cold solution of sodium methoxide (0.33 g, 6.1 mmol) inmethanol (50 mL). The suspension is refluxed for 21 hours, cooled,diluted with water and extracted with dichloromethane. The organicextracts are dried over Na₂SO₄, filtered and concentrated under vacuum.The resulting residue is purified by flash column chromatography (1:5ethyl acetate/hexanes) to afford the title compound (0.211 g). ¹H NMR(200 MHz, CDCl₃): δ 6.33–6.26 (m, 1H), 5.88–5.80 (m, 1H), 4.23 (q, 2H),4.19–4.10 (m, 2H), 3.41 (s, 3H), 1.31 (t, 3H).

EXAMPLE A18

General Method A

A solution of substrate andN-(methoxymethyl)-N-(trimethyl-silylmethyl)benzylamine (1.3 eq.) indichloromethane at 0° C. is treated with trifluoroacetic acid (0.07 eq).The mixture is stirred at room temperature for 3 hours, diluted withdichloromethane and washed successively with a saturated NaHCO₃ solutionand brine. The organic extracts are dried over Na₂SO₄, filtered, andconcentrated under vacuum to afford the title compounds.

The examples below (Example A18a–e) were prepared according to GeneralMethod A.

(a) 1-Benzyl-3-methoxymethylpyrrolidine-3-carboxylic acid ethyl ester(¹H NMR (200 MHz, CDCl₃): δ 7.45–7.16 (m, 5H), 4.19 (q, 2H), 3.78–3.67(m, 2H), 3.55 (s, 2H), 3.31 (s, 3H), 3.11–2.92 (m, 1H), 2.89–2.49 (m,2H), 2.42–2.21 (m, 2H), 1.99–1.78 (m, 1H), 1.26 (t, 3H)) from2-methoxymethylacrylic acid ethyl ester (Example A17).

(b) 1-(1-Benzyl-4,4-dimethylpyrrolidin-3-yl)ethanone (¹H NMR (200 MHz,CDCl₃): δ 7.36–7.22 (m, 5H), 3.60 (d, 2H), 3.05–2.20 (m, 5H), 2.15 (s,3H), 1.30 (s, 3H), 0.96 (s, 3H)) from mesityl oxide.

(c) 1-Benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester (¹H NMR(200 MHz, CDCl₃): δ 7.44–7.13 (m, 5H), 4.21–4.04 (q, 1H), 3.71–3.49 (m,3H), 2.94–2.71 (m, 3H), 2.61–2.41 (m, 2H), 2.28–2.04 (m, 1H), 1.32–1.18(t, 3H), 1.16–1.04 (d, 3H). MS ES: m/z 248 (MH⁺)) from ethyl crotonate.

(d) Pyrrolidine-3-carboxylic acid tert-butyl ester (MS ES: m/z 172(MH⁺)) from tert-butylacrylate.

(e) Ethyl 1,3-dibenzyl-3-pyrrolidinecarboxylic acid (MS EI+: m/z 324(MH⁺)) from ethyl-2-phenylmethylacrylic acid (Vassailiou S., Mucha A.,Cuniasse P., Georgiadis D., Lucet-Levannier K., Beau F., Kannan R, etal., J. Med. Chem., 1999; 42(14):2610–2620).

EXAMPLE A19 Synthesis of(1-Benzyl-3-methoxymethylpyrrolidin-3-yl)methanol

A solution of 1-benzyl-3-methoxymethylpyrrolidine-3-carboxylic acidethyl ester (Example A18a, 2.30 g, 8.3 mmol) in anhydroustetrahydrofuran (10 mL) is added dropwise to an ice-cold suspension oflithium aluminum hydride (0.821 g, 22 mmol) in tetrahydrofuran (50 mL).The resulting mixture is stirred at room temperature for 18 hours,cooled and quenched by the sequential dropwise addition of 1N sodiumhydroxide and water. The solids are removed by filtration, re-suspendedin hot tetrahydrofuran and filtered. The combined filtrates areconcentrated in vacuo and the residue is partitioned betweendichloromethane and water. The organic extracts are dried over Na₂SO₄,filtered and concentrated under vacuum to afford the title compound(1.71 g). 1N NMR (200 MHz, CDCl₃): δ 7.41–7.17 (m, 5H), 3.84–3.43 (m,4H), 3.34 (s, 2H), 3.32 (s, 3H), 2.85–2.60 (m, 2H), 2.54–2.14 (m, 3H),1.98–1.50 (m, 2H).

EXAMPLE A202-(1-Benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)isoindole-1,3-dione

A solution of (1-benzyl-3-methoxymethylpyrrolidin-3-yl)methanol (ExampleA19, 1.71 g, 7.27 mmol), triphenylphosphine (2.16 g, 8.22 mmol),phthalimide (1.14 g, 7.73 mmol), and anhydrous tetrahydrofuran is cooledto 0° C. and treated with diethyl azodicarboxylate (1.62 g, 9.31 mmol).The resulting mixture is stirred at room temperature for 18 hours andconcentrated under vacuum. The residue is purified by flash columnchromatography (1:5 ethyl acetate/hexanes) to afford the title compound,(0.58 g) as a solid. ¹H NMR (200 MHz, CDCl₃): δ 7.91–7.80 (m, 2H),7.78–7.66 (m, 2H), 7.39–7.11 (m, 5H), 3.95–3.72 (m, 2H), 3.65–3.40 (m,2H), 3.31 (s, 2H), 3.27 (s, 3H), 2.72–2.34 (m, 4H), 2.02–1.82 (m, 1H),1.76–1.56 (m, 1H). MS ES: m/z 365 (MH⁺).

EXAMPLE A21 Synthesis of 1-Benzylpiperidine-3-carboxylic acid benzylester

To a solution added of nipecotic acid (8.0 g, 61.9 mmol) inN,N-dimethylformamide (80 mL) is benzyl bromide (31.8 g, 186 mmol) andpotassium carbonate (42.8 g, 310 mmol). The mixture is heated at 70° C.for 18 hours and diluted with ethyl acetate and water. The organicextract is washed with 1.0 M hydrochloric acid, water and brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue is purifiedby column chromatography (1:7 ethyl acetate/hexanes) to afford the titlecompound (8.6 g). ¹H NMR (200 MHz, DMSO-d₆): δ 7.27–7.42 (m, 10H), 5.07(s, 2H), 3.45 (s, 2H), 2.88–2.49 (m, 3H), 2.32–1.32 (m, 6H).

EXAMPLE A22 Synthesis of 1-Benzylpiperidine-3-carboxylic acid

To a solution 3.0 g (9.7 mmol) of 1-benzylpiperidine-3-carboxylic acidbenzyl ester (Example A21) in methanol (20 mL) was added 1N sodiumhydroxide (20 mL), and the reaction is stirred at room temperature for18 hours. The methanol is removed in vacuo and the basic aqueoussolution is acidified to pH 4 with 1.0 M hydrochloric acid. Afterwashing with ethyl acetate, the aqueous acid layer is lyophilized. Thesolid is suspended in methanol (10 mL), stirred for 10 minutes andfiltered. The filtrate is evaporated in vacuo to afford the titlecompound (2.0 g). ¹H NMR (200 MHz, DMSO-d₆): δ 7.38–7.23 (m, 5H), 3.58(s, 2H), 2.98–2.40 (m, 3H), 2.30–1.25 (m, 6H).

EXAMPLE A23

General procedure A

Methyl lithium (1.1 eq.) is added dropwise to a −70° C. solution ofsubstrate in tetrahydrofuran (15 mL). The resulting mixture is stirredat −70° C. for 1 hour, and then warmed to room temperature for 18 hours.The reaction is diluted with ice water and ether and the organic layeris separated. The aqueous layer is extracted with ether and the combinedextracts are dried with Na₂SO₄ and concentrated in vacuo to afford thetitle compound.

The following compounds are prepared according to general procedure A.

(a) 1-(1-Benzylpiperidin-3-yl)ethanone (¹H NMR (200 MHz, DMSO-d₆): δ7.38–7.22 (m, 5H), 3.45 (s, 2H), 2.85–2.48 (m, 3H), 2.05 (s, 3H),2.16–1.06 (m, 6H)) from 1-benzylpiperidine-3-carboxylic acid (ExampleA22).

(b)-(1-Benzyl-4-methylpyrrolidin-3-yl)ethanone (¹H NMR (200 MHz, CDCl₃):δ 7.42–7.18 (m, 5H), 3.71–3.45 (m, 3H), 2.89–2.33 (m, 5H), 2.16 (s, 3H),1.12 (d, 3H)) from 1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethylester (Example A18c).

EXAMPLE A24 Synthesis of 5-Benzyl-5-azaspiro[2,4]heptane-7-carboxylicacid amide

5-Benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid amide (3.32 g) isprepared from 5-benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid (ExampleA28b, 5.0 g, 21.64 mmol) in dichloromethane by conversion to the acidchloride using oxalyl chloride (5.0 mL, 65 mmol) andN,N-dimethylformamide (3 drops). The mixture is allowed to stir for 2hours then concentrate in vacuo. The residue is redissolved indichloromethane and the mixture is again concentrated in vacuo. Theresidue is dissolved in ether and treated with a solution of ammonia inether. After 1 hour, the mixture is concentrated in vacuo to provide thetitle compound. ¹H NMR (CDCl₃): δ 7.6 (bs, 1H), 7.38–7.23 (m, 5H), 5.42(bs, 1H), 3.75–3.57 (m, 2H), 3.19 (d, 1H), 2.83–2.64 (m, 2H), 2.4 (d,2H), 0.96–0.58 (m, 4H).

EXAMPLE A25 Synthesis of 2(1-Benzylpyrrolidin-3-yl)propan-2-ol

To a 5° C. solution of 1-benzylpyrrolidine-3-carboxylic acid ethyl ester(0.467 g, 2.0 mmol) in tetrahydrofuran (25 mL) is added an etherialsolution of methylmagnesium bromide (3.3 mL, 10 mmol). The reactionmixture is stirred at room temperature for 2 hours, cooled to 0° C. andsaturated aqueous ammonium chloride (10 mL) is added followed by water(10 mL). The mixture is extracted with ethyl acetate (2×100 mL) and thecombined organic extracts are washed with brine, dried over Na₂SO₄,filtered and concentrated under vacuum to afford the title compound(0.43 g). ¹H NMR (200 MHz, CDCl₃): δ 7.30–7.22 (m, 5H), 3.59 (s, 2H),3.0 (bs, 1H), 2.80–2.66 (m, 2H), 2.48–2.30 (m, 2H), 2.20–2.05 (m, 1H),1.94–1.80 (m, 2H), 1.19 (s, 3H), 1.16 (s, 3H).

EXAMPLE A26 Synthesis of2-Benzyloctahydropyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butylester

2-Benzyloctahydropyrrolo[3,4-c]pyridine (21.6 g, 100 mmol [Himmler T.,Petersen U., Bremm K-D., Endermann R., Stegemann M., Wetzstein H-G.,1995, U.S. Pat. No. 5,578,604] is dissolved in 1000 mL ofdichloromethane containing triethylamine (16.7 mL, 120 mmol). Thendi-t-butyldicarbonate (22.6 g, 120 mmol) is added and the mixture isstirred at room temperature for 18 hours. The organic layer is washedwith saturated NaHCO₃, brine, dried, and concentrated to provide 30 g ofthe title compound as an oil; MS EI+: 318 (MH⁺).

EXAMPLE A27 Synthesis of octahydropyrrolo[3,4-c]pyridine-5-carboxylicacid tert-butyl ester

2-Benzyloctahydropyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butylester (Example A26, 24.98 g, 78.8 mmol) in 400 mL of methanol is treatedwith 2.5 g of 20% Pd/C and shaken for 20.5 hours under 50 PSI ofhydrogen. The solution is filtered and concentrated to afford 17.8 g ofthe title compound as a solid. MS APCI: m/z 228 (MH⁺).

EXAMPLE A28 (a) Synthesis of 1,3-Dibenzylpyrrolidine-3-carboxylic acid

To a solution of 1,3-dibenzylpyrrolidine-3-carboxylic acid ethyl ester(Example A18e, 13.1 g, 41 mmol) in 250 mL of methanol is added 2N NaOH(46 mL, 92 mmol) and the reaction is heated to reflux for 24 hours. Thesolution is cooled, concentrated, redissolved in water and extractedwith ether. The pH of the aqueous layer is adjusted to 7 and theprecipitated solid is collected, to give 9.3 g of the title compound, MSEI+: m/z 296 (MH⁺), mp 209–210° C.

(b) 5-Benzyl-5-azaspiro[2,4]heptane-7-carboxylic acid (MS ES: m/z 232)from 5-benzyl-7-ethoxycarbonyl-5-azaspiro[2,4]heptane (A1) using themethod of Example A28a

EXAMPLE A29 Synthesis of 1,3-Dibenzylpyrrolidine-3-carboxylic acid amide

A mixture of 1,3-dibenzylpyrrolidine-3-carboxylic acid (Example A28, 4.0g, 13.5 mmol), 1,1′-carbonyldiimidazole (2.42 g, 14.9 mmol), andtriethylamine (2.08 mL, 14.9 mmol) in tetrahydrofuran (100 mL) is heatedat reflux for 1.5 hours. The solution is cooled, poured into NH₄OH (300mL), and stirred for 18 hours. The mixture is extracted with chloroform,the organic layer is washed with water, dried, and concentrated toafford 4.13 g of the title compound as an oil; MS El+: m/z 295 (MH⁺).

EXAMPLE A30 Synthesis of (3-Phenylpyrrolin-3-yl)carbamic acid tert-butylester

(1-Benzyl-3-phenylpyrrolidin-3-yl)carbamic acid tert-butyl ester (HagenS. E., Domagala J. M., Heifetz C. L., Sanchez J. P., Solomon M., J. Med.Chem., 1990; 33(2):849–854) (2.79 g, 7.9 mmol) in 100 mL of methanol istreated with 1.0 g of 20% Pd/C and shaken for 17 hours under 50 psi ofhydrogen. The solution is filtered and concentrated to afford 2.07 g ofthe title compound as a foam; MS EI+: m/z 263 (MH⁺).

The compounds of the present invention are potent inhibitors ofbacterial growth both in animals and on surfaces, and also areinhibitors of bacterial enzymes. The invention compounds have beenevaluated in a number of standard in vitro and in vivo assays routinelyused by those in the antibacterial art to measure antibacterial activityof test compounds.

Antibacterial Assay

The compounds of the present invention are tested against an assortmentof Gram negative and Gram positive organisms using standardmicrotitration techniques (Cohen et al., Antimicrob. Agents Chemother.,1985; 28:766; Heifetz et al., Antimicrob. Agents Chemother, 1974;6:124). The results of the evaluation of representative3-aminoquinazolin-2,4-diones of Formula I are shown in Table 2 andcompared to two 3-hydroxyquinazolin-2,4-diones.

DNA Gyrase Assay

The effects of invention compounds on the activity of DNA gyrase isdetermined in the supercoiling inhibition assay, following reactionconditions recommended by the enzyme supplier (Lucent, Ltd., Leicester,UK). Reactions are performed in buffer G (35 mM Tris-HCl (pH 7.5), 24 mMKCl, 4 mM MgCl₂, 2 mM DTT, 1.8 mM spermidine, 1 mM ATP, 0.1 mg/mL bovineserum albumin). Relaxed plasmid pBR322 (0.25 μg, Lucent, Ltd.,Leicester, UK) is reacted with 1 U E. coli gyrase (Lucent, Ltd.,Leicester, UK), in the absence or presence of test compounds, for 30minutes at 37° C. Reactions are stopped by the addition of SDS andproteinase K to respective final concentrations of 1% and 0.5 mg/mL.After an additional 30 minutes at 37° C., one-tenth volume of 10Xloading buffer (0.3% bromophenol blue, 16% Ficoll, 10 mM Na₂HPO₄) isadded, and reactions are loaded onto agarose gels and electrophoresed.The concentration of representative invention compounds of Formula Iinhibiting 50% of the supercoiling activity of DNA gyrase is given as anIC₅₀ and recorded in Table 2.

TABLE 2 Antibacterial and E. coli gyrase Activities Minimum InhibitoryConcentrations μg/mL E. coli Gram Negatives Gram Positives gyrase E.coli E. coli E. coli E. faecalis S. aureus S. pyogenes IC₅₀ CompoundNumber or Structure MC4100 B90 Tol C RB1 29213 C203 (μM)  1 2.0 1.0 0.251.0 0.5 0.13 1.0  2 16.0 4.0 2.0 >64 >64 >64 26.0  7 2.0 0.5 0.25 8.08.0 4.0 1.3  9 2.0 1.0 0.5 32.0 16.0 16.0 3.0 11 2.0 0.5 0.25 8.0 8.04.0 11.0 12 16.0 0.25 0.13 4.0 2.0 8.0 2.1 14 4.0 0.25 0.5 8.0 8.0 4.02.4

1.0 0.25 0.25 4.0 4.0 2.0 0.9

8.0 2.0 1.0 64.0 32.0 32.0 5.0

The in vivo activity of invention compounds is evaluated according tothe procedure of Miller et al., Proc. Soc. Exp. Biol. Med., 1944;57:261. The median protective dose (PD₅₀) is determined in mice givenlethal systemic infections. Two 3-aminoquinazolin-2,4-diones of theinvention are compared to a 3-hydroxyquinazolin-2,3-dione, and theresults are presented in Table 3. The results establish the unexpectedsuperiority of the 3-amino invention compounds compared to similar3-hydroxy analogs.

TABLE 3 In Vivo Median Protective Dose (PD₅₀) in Mice PD50 CompoundNumber or Structure Organism (mg/kg)  1 S. pyogenes 12 10 E. coli 72

S. pyogenes >100Cross Resistance Antibacterial Assay

The compounds of the present invention are tested against an assortmentof ciprofloxacin resistant E. coli and S. aureus organisms describedbelow using standard microtitration techniques (Cohen, et al.,Antimicrob. Agents Chemother, 1985; 28:766; Heifetz, et al., Antimicrob.Agents Chemother, 1974; 6:124). The results of the evaluation are shownin Table 4 and compared to two 3-hydroxyquinazolin-2,4-diones.

E. coli and S. aureus organisms:

-   E. coli JL4: E. coli W3110+Tol C⁻(Tol C pump deficient strain    with E. coli W3110 background)-   E. coli LLM-1: Isogenic to E. coli JL4 with a D87G mutation    (aspartic acid to glycine at position 87) in the QRDR (quinolone    resistance determining region)-   S. aureus UC-76: Typical sensitive laboratory strain (Wild type)-   S. aureus 2552: Isogenic to S. aureus UC-76, with upregulated norA    pump-   S. aureus 2554: Isogenic to S. aureus 2552, with point mutation at    position 80 of grlA.subunit-   S. aureus 2558: Isogenic to S. aureus 2554, with point mutation at    position 84 of gyrA subunit

TABLE 4 Antibacterial Activities Against Ciprofloxacin Resistant StrainsMinimum Inhibitory Concentrations μg/mL E. coli E. coli S. aureus S.aureus S. aureus S. aureus Compound Number or Structure JL4 LLM1 UC-762552 2554 2558  1 0.13 0.5 0.13 1 1 1  3 0.5 1 1 2 2 4 12 0.06 0.25 1 11 2

0.25 4 4 32 32 >64

0.5 2 4 >64 >64 >64

The quinolone mimics provided by this invention display Gram-negativeand Gram-positive activity. The compounds also show inhibition ofbacterial DNA gyrase/activity. The compounds demonstrate in vivoprotective activity in mice and are not highly cytotoxic to mammaliancells, thus indicating selectivity for bacteria. The compounds ofFormula I are thus useful for treating and preventing bacterial diseaseand growth in both animals and on surfaces. The compounds can be appliedto wood and metal surfaces, for instance, to eliminate bacterial growth.The compounds can be administered to animals such as humans, horses,dogs, sheep, and cattle to prevent and treat bacterial infections.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms for convenientadministration to animals. Thus, the compounds of the present inventioncan be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds of the present invention can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally. Itwill be obvious to those skilled in the art that the following dosageforms may comprise as the active component, either a compound of FormulaI or a corresponding pharmaceutically acceptable salt of a compound ofFormula I. The formulations typically will comprise from about 1 toabout 95 percent by weight of the active invention compound. Thecompounds can be dissolved or suspended in liquids, such as ethanol, andapplied to wood or metal surfaces to prevent and/or kill bacterialgrowth.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or, synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of invention compound in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg, preferably from 0.5 mg to 100mg, according to the particular application and the potency of theactive component as determined by a skilled physician. The compositioncan, if desired, also contain other compatible therapeutic agents.

In therapeutic use as agents for the treatment of infections caused by abacteria, the compounds utilized in the pharmaceutical method of thisinvention are administered at the initial dosage of about 0.01 mg toabout 500 mg/kg daily. A daily dose range of about 0.01 mg to about 100mg/kg is preferred. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the particular compound being employed. Determination ofthe proper dosage for a particular situation is within the skill of themedical art. Generally, treatment is initiated with smaller dosageswhich are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day, if desired.

The following additional examples illustrate typical formulations foruse according to the invention.

EXAMPLE 37

1. Tablet Formulation Ingredient Amount (mg) Compound No. 10 50Cornstarch (mix) 15 Cornstarch (paste) 5 Lactose 50 Calcium stearate 2Dicalcium phosphate 28 150

Compound 10 is blended to uniformity with the cornstarch mix, lactose,and dicalcium phosphate. The cornstarch paste is prepared as a 10%aqueous paste, and it is blended to uniformity with the other mixture.The wet granulation is passed through a standard 8-mesh screen. The wetgranules are dried and then blended to uniformity with the calciumstearate and pressed into a tablet. Such tablets are administered orallyto patients suffering from bacterial infections at the rate of from oneto about four times a day.

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein: R₁ and R₃independently are H, C₁–C₁₂ alkyl and substituted alkyl, C₂–C₁₂ alkenyland substituted alkenyl, C₂–C₁₂ alkynyl and substituted alkynyl, C₃–C₁₂cycloalkyl and substituted cycloalkyl, aryl and substituted aryl,heterocyclic and substituted heterocyclic, or heteroaryl and substitutedheteroaryl; R₅, R₆, and R₈ independently are H, (O)_(n)C₁–C₁₂ alkyl andsubstituted alkyl, (O)_(n)C₂–C₁₂ alkenyl and substituted alkenyl,(O)_(n)C₂–C₁₂ alkynyl and substituted alkynyl, wherein n is 0 or 1,halo, NO₂, CN, NR′R″; R′ and R″ independently are H, C₁–C₁₂ alkyl andsubstituted alkyl, C₂–C₁₂ alkenyl and substituted alkenyl, C₂–C₁₂alkynyl and substituted alkynyl, CO—C₁–C₁₂ alkyl and substituted alkyl,or R′ and R″ taken together with the nitrogen to which they are attachedform a 3- to 7-membered ring containing from 1 to 3 heteroatoms selectedfrom N, O, and S, said ring being unsubstituted or substituted with upto 4 substituent groups; R₁ and R₈ can be taken together with the atomsto which they are attached to form a cyclic ring having from 1 to 3heteroatoms selected from N, O, and S, and optionally substituted by R′and R″; R₇ is C₂–C₁₂ alkenyl and substituted alkenyl, C₂–C₁₂ alkynyl andsubstituted alkynyl, NO₂, CN, NR′R″, COOR′, aryl, fused aryl,heterocyclic, fused heterocyclic, bicyclic heterocyclic, or spiroheterocyclic, wherein all ring groups can be substituted; and J and Kare C.
 2. A compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein: R₁ and R₃independently are H, C₁–C₁₂ alkyl and substituted alkyl, C₂–C₁₂ alkenyland substituted alkenyl, C₂–C₁₂ alkynyl and substituted alkynyl, C₃–C₁₂cycloalkyl and substituted cycloalkyl, aryl and substituted aryl,heterocyclic and substituted heterocyclic, or heteroaryl and substitutedheteroaryl; R₆ and R₈ independently are H, (O)_(n)C₁–C₁₂ alkyl andsubstituted alkyl, (O)_(n)C₂–C₁₂ alkenyl and substituted alkenyl(O)_(n)C₂–C₁₂ alkynyl and substituted alkynyl, wherein n is 0 or 1,halo, NO₂, CN, NR′R″; R₇ is C₂–C₁₂ alkenyl and substituted alkenyl,C₂–C₁₂ alkynyl and substituted alkynyl, NO₂, CN, NR′R″, COOR′, aryl,fused aryl, heterocyclic, fused heterocyclic, bicyclic heterocyclic, orspiro heterocyclic, wherein all ring groups can be substituted.
 3. Acompound of Formula V

or a pharmaceutically acceptable salt thereof, wherein: R₁ and R₃independently are H, C₁–C₁₂ alkyl and substituted allyl, C₂–C₁₂ alkenyland substituted alkenyl, C₂–C₁₂ alkynyl and substituted alkynyl, C₃–C₁₂cycloalkyl and substituted cycloalkyl, aryl and substituted aryl,heterocyclic and substituted heterocyclic, or heteroaryl and substitutedheteroaryl; R₆ and R₈ independently are H, (O)_(n)C₁–C₁₂ alkyl andsubstituted alkyl, (O)_(n)C₂–C₁₂ alkenyl and substituted alkenyl,(O)_(n)C₂–C₁₂ alkynyl and substituted alkynyl, wherein n is 0 or 1,halo, NO₂, CN, NR′R″; R′ and R″ independently are H, C₁–C₁₂ alkyl andsubstituted alkyl, C₂–C₁₂ alkenyl and substituted alkenyl, C₂–C₁₂alkynyl and substituted alkynyl, CO—C₁–C₁₂ alkyl and substituted alkyl,or R′ and R″ taken together with the nitrogen to which they are attachedform a 3- to 7-membered ring containing from 1 to 3 heteroatoms selectedfrom N, O, and S; said ring being unsubstituted or substituted with upto 4 substituent groups.
 4. A compound of claim 1 wherein R₇ is selectedfrom:


5. A compound of claim 4 wherein R₇ is pyrrolidinyl, substitutedpyrrolidinyl, piperazinyl, substituted piperazinyl, piperidinyl orsubstituted piperidinyl.
 6. A compound selected from:3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-piperazin-1-yl-1H-quinazoline-2,4-dione;3-Amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-2,4-dione;3-Amino-7-((S)-3-N-methylaminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-8-chloro-1-(2,4-difluoroanilino)-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-6,8-difluoro-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-aminopyrrolidin-1-yl]-1-cyclopropylamino-5,8-difluoro-1H-quinazoline-2,4-dione;3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-5,6,8-trifluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;7-((S)-3-Aminopyrrolidin-1-yl)-1-cyclopropyl-3,5-diamino-6,8-difluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-hydroxymethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminoethylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-6-fluoro-1-isopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolin-1-yl)-1-sec-butyl-8-chloro-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[3-aminopyrrolidin-1-yl]-8-chloro-1-cyclobutylamino-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-6-chloro-1-cyclopropyl-8-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropylmethyl-8-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropylmethyl-8-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-ethyl-8-fluoro-1H-quinazoline-2,4-dione;3-Amino-1-ethyl-6-fluoro-7-[(R)-3-(1-amino-1-methylethyl)-pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-fluoro-6-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-8-ethoxy-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-carbonitrile;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-[1,2,3-triazol]-1-yl-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;5-Amino-9-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione;5-Amino-9-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-fluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione;2-Amino-8-((S)-3-aminopyrrolidin-1-yl)-9-fluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione;2-Amino-8-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-9-fluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione;3-Amino-7-((S)-3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione; 3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-c]pyridin-2-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-(octahydropyrrolo[3,4-b]pyridin-2-yl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;trans-3-Amino-7-(3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[(R)-3-((R)-1-methylamino-ethyl)pyrrolidin-1-yl]-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-aminopropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;3-Amino-7-[7-(1-aminoethyl)-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)piperidine-3-carboxylicacid amide;3-Amino-[7-trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-{3-[(2,2,2-trifluoro-ethylamino)methyl]pyrrolidin-1-yl}-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(5-methylhexahydro-pyrrolo[3,4-c]pyrrolo-2-yl)-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-7-(2,7-diazaspiro[4.4]non-2-yl)-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-benzylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-(3-hydroxyimino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione;3-Amino-7-[trans-3-amino-4-trifluoromethylpyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[(R)-3-(S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;3-Amino-7-(trans-3-amino-4-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[trans-3-amino-4-(4-hydroxyphenyl)pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;N-[1-(3-Amino-8Chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;3-Amino-7-(3-aminomethylpiperidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-8-chloro-1-cyclopropyl-6-fluoro-7-[3-(isopropylamino-methyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylpyrrolidin-1-yl)-6,8-dichloro-1-cyclopropyl-1H-quinazoline-2,4-dione;N-[1-(3-Amino-8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-ylmethyl]methanesulfonamide;3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[3-(1-aminoethyl)-3-methoxypyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[3-(1-aminoethyl)-3-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-(S)-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-methoxymethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(trans-3-aminomethyl-4-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[3-(aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-phenylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(7-aminomethyl-5-azaspiro[2,4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-amino1-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione;3-Amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3(-((S)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-ethyl-6-fluoro-1H-quinazoline-2,4-dione;1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylicacid trifluoroacetate;1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-7-yl)pyrrolidine-3-carboxylic acidtrifluoroacetate;3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4dione;3-Amino-7-(1-aminomethyl-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(S)-3-((R)-1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-(octahydropyrrolo[3,4-b]pyridin-6-yl)-1H-quinazoline-2,4-dione;3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-diode;3-Amino-7-(trans-3-amino-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylmorpholin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[3-(1-aminoethyl)-1-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione,3-Amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methyl-7-pyrrolidin-1yl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-pyrrolidin-1yl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin-1-yl]-8-methyl-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(1-hydroxy-1-methylethyl)-pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-5-methyl-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;(S)-1-[(R)-1-(3-Amino-1-cyclopropyl-7-[3-(1-ethylaminoethyl)pyrrolidin-1-yl)-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-7-[(R)-3-((S)-1-ethylaminoethyl)pyrrolidin-1-yl]-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(6-amino-1-methyl-3-azabicyclo[3.2.0]hept-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;cis-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;trans-3-Amino-7-(3-aminomethyl-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(1-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyloctahydroisoindol-2-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-aminoethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-(1-amino-1-methylethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-7-[3-(isopropylaminomethyl)pyrrolidin-1-yl]-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)-octahydropyrrolo[3,4-b]pyridin-6-yl-1H-quinazoline-2,4-dione;3-Amino-7-(3-amino-4-fluoromethylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethyl-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-[(R)-3-((S)-1-methylaminoethyl)pyrrolidin-1-yl]-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminoazetidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-diode;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-quinazoline-2,4-dione;{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(R)-2-Amino-2-[(R)-1-(3-amino-1cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(R)-2-Amino-2-[(3R,4S)-1-(3-amino1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-(R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-(-1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-(R)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-(S)-1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-(R)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methooxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((S)-1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((R)-1-amino-2-ethoxyethyl-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-4-((R)-1-amino-2-ethoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((S)-1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((S)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4S)-3-((S)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1quinazoline-2,4-dione;3-Amino-7-[(R)-3-((R)-1-amino-3-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;3-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione;-Amino-7-[(3R,4R)-3-((R)-1-amino-3-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxy-1H-quinazoline-2,4-dione;{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(R)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}urea;{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{(R)-2-Amino-2-[(3R,4S)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{(S)-2-Amino-2-[(3R,4R)-1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-methylpyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4-fluoropyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;{2-Amino-2-[(1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}urea;3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[4,3-d]pyrimidine-2,4-dione;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;3-Amino-7-[3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-(3-(1-aminoethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-1-methylethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-fluoropyrrolidin-1-yl-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[4-(1-amino-2-methoxyethyl)-3,3dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-phenoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[4-(1-amino-2-phenoxyethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-ethoxyethyl)-4,4-dimethylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)pyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;3-Amino-7-[3-(1-amino-2-methoxypropyl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione;{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)pyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-methylpyrrolidin-3-yl]ethylurea;(2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-1-fluoropyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4-fluoropyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;{2-Amino-2-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4tetrahydropyrido[3,2-d]pyrimidin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethylurea;3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylphenyl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylphenyl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-aminomethylphenyl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-6fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(2-aminomethylthiazol-4-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(2-aminomethylthiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-[2-(1-aminoethyl)thiazol-4-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(5-aminomethylthiophen-3-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(5-aminomethylthiophen-3-yl)-8-methoxy-1cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminomethyl-3,3difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminomethyl-3,3difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione3-Amino-7-(4-aminomethyl-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4–4-dione;3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-chloro-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methyl-1-cyclopropyl-1H-quinazoline-2,4-dione;3-Amino-7-(4-(1-amino-1-methylethyl)-3,3-difluoropyrrolidin-1-yl)-8-methoxy-1-cyclopropyl-1-H-quinazoline-2,4-dione;3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-5,8-dimethyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-5-methyl-1H-quinazoline-2,4-dione;3-Amino-7-(3-(1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-8-methoxy-5-methyl-1H-quinazoline-2,4-dione;3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-5-methyl-1H-quinazoline-2,4-dione;and3,8-Diamino-7-[3-(1-aminoethyl)pyrrolidin-1-yl]-1-cyclopropyl-5-methyl-1H-quinazoline-2,4-dione.7. A pharmaceutical composition comprising a compound of claim 1 admixedwith a carrier, diluent, or excipient.
 8. A pharmaceutical compositioncomprising a compound of claim 2 admixed with a carrier, diluent, orexcipient.
 9. A pharmaceutical composition comprising a compound ofclaim 3 admixed with a carrier, diluent, or excipient.
 10. Apharmaceutical composition comprising a compound of claim 6 admixed witha carrier, diluent, or excipient.
 11. A method of treating a bacterialinfection in a mammal comprising administering to the mammal anantibacterial effective amount of a compound of claim 1, wherein thebacterial infection is caused by E. faecalis, S. aureus, S. pyogenes orE. coli.
 12. A method of treating a bacterial infection in a mammalcomprising administering to the mammal an antibacterial effective amountof a compound of claim 2, wherein the bacterial infection is caused byE. faecalis, S. aureus, S. pyogenes or E. coli.
 13. A method of treatinga bacterial infection in a mammal comprising administering to the mammalan antibacterial effective amount of a compound of claim 3, wherein thebacterial infection is caused by E. faecalis, S. aureus, S. pyogenes orE. coli.
 14. A method of treating a bacterial infection in a mammalcomprising administering to the mammal an antibacterial effective amountof a compound of claim 6, wherein the bacterial infection is caused byE. faecalis, S. aureus, S. pyogenes or E. coli.